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Shen D, Chen J. Cardiac Macrophages Promote Polarization of Macrophages toward M2 Phenotype to Improve Myocardial Remodeling via NGAL after Myocardial Infarction. Cell Biochem Biophys 2025:10.1007/s12013-025-01726-1. [PMID: 40138155 DOI: 10.1007/s12013-025-01726-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2025] [Indexed: 03/29/2025]
Abstract
Several studies have shown that the number of circulating neutrophils or the levels of their secreted factors, including Neutrophil Gelatinase-Associated Lipocalin (NGAL), in plasma are associated with the prognosis and mortality of patients with myocardial infarction (MI). However, the underlying mechanisms remain unclear. MI was induced in mice by permanent ligation of the left anterior descending coronary artery. Mice were then intraperitoneal administered IgG control, anti-Ly6G antibody and recombinant mouse NGAL at 1 h after the surgery and once daily from day 1-14 after surgery. At days 1, 3, 7, and 14 after surgery, echocardiogram showed that neutrophils significantly attenuates LV remodeling and reserves contractile function after MI compared with isotype control group. Flow cytometry revealed that the myocardial infiltration of macrophages decreased in MI mice with Ly6G-depleted. Moreover, WB and flow cytometry showed that macrophages differentiated by exposure to CM and NGAL, especially the latter, displayed a M2-like phenotype, expressing higher MerTK level than control M0 macrophages and the cells exposed to MPO. Meanwhile, flow cytometry indicated that the ability to remove dead cells of M2c-like macrophages triggered by NGAL significantly enhanced compared to those control M0 macrophages and the cells exposed to MPO. Most importantly, we validated that the decrease of M2c macrophage polarization in MI caused by neutrophils depletion can be reversed by NGAL in vivo. NGAL successfully induced the polarization of macrophages into M2c type. Furthermore, cardiac macrophages improve myocardial remodeling and cardiac function by inducing the polarization of M2c-like macrophages via NGAL after MI.
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Affiliation(s)
- Donghui Shen
- Department of Endocrinology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Jiabing Chen
- Department of Cardiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
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Zhang ZX, Peng J, Ding WW. Lipocalin-2 and intestinal diseases. World J Gastroenterol 2024; 30:4864-4879. [PMID: 39679305 PMCID: PMC11612708 DOI: 10.3748/wjg.v30.i46.4864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 09/25/2024] [Accepted: 11/04/2024] [Indexed: 11/21/2024] Open
Abstract
Dysfunction of the intestinal barrier is a prevalent phenomenon observed across a spectrum of diseases, encompassing conditions such as mesenteric artery dissection, inflammatory bowel disease, cirrhosis, and sepsis. In these pathological states, the integrity of the intestinal barrier, which normally serves to regulate the selective passage of substances between the gut lumen and the bloodstream, becomes compromised. This compromised barrier function can lead to a range of adverse consequences, including increased permeability to harmful substances, the translocation of bacteria and their products into systemic circulation, and heightened inflammatory responses within the gut and beyond. Understanding the mechanisms underlying intestinal barrier dysfunction in these diverse disease contexts is crucial for the development of targeted therapeutic interventions aimed at restoring barrier integrity and ameliorating disease progression. Lipocalin-2 (LCN2) expression is significantly upregulated during episodes of intestinal inflammation, making it a pivotal indicator for gauging the extent of such inflammatory processes. Notably, however, LCN2 derived from distinct cellular sources, whether intestinal epithelial cells or immune cells, exhibits notably divergent functional characteristics. Furthermore, the multifaceted nature of LCN2 is underscored by its varying roles across different diseases, sometimes even demonstrating contradictory effects.
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Affiliation(s)
- Zhong-Xu Zhang
- Department of Trauma and Acute Care Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Jian Peng
- Department of Trauma and Acute Care Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Wei-Wei Ding
- Department of Trauma and Acute Care Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, Jiangsu Province, China
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Dimopoulou C, Guerra PR, Mortensen MS, Kristensen KA, Pedersen M, Bahl MI, Sommer MAO, Licht TR, Laursen MF. Potential of using an engineered indole lactic acid producing Escherichia coli Nissle 1917 in a murine model of colitis. Sci Rep 2024; 14:17542. [PMID: 39080343 PMCID: PMC11289411 DOI: 10.1038/s41598-024-68412-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 07/23/2024] [Indexed: 08/02/2024] Open
Abstract
The gut microbiome is a significant factor in the pathophysiology of ulcerative colitis (UC), prompting investigations into the use of probiotic therapies to counter gastrointestinal inflammation. However, while much attention has been given to the therapeutic potential of microbes at the species and strain level, the discovery and application of their metabolic products may offer more precise and controlled solutions in battling disease. In this work, we examined the therapeutic potential of indole lactic acid (ILA) to alleviate inflammation in a murine model of colitis. A previously constructed ILA-producing Escherichia coli Nissle 1917 strain (EcN aldh) and its isogenic non-ILA producing counterpart (EcN) were studied in a murine model of Dextran Sodium Sulfate (DSS) induced colitis. The colitic animals suffered from severe colitic symptoms, with no differentiation between the groups in body weight loss and disease activity index. However, three days after cessation of DSS treatment the EcN aldh-treated mice showed signs of reduced intestinal inflammation, as manifested by lower concentrations of fecal lipocalin-2. Additionally, expression analysis of the inflamed tissue revealed distinct effects of the EcN aldh strain on proteins associated with intestinal health, such as TFF3, occludin and IL-1β expression. These results show no impact of EcN or EcN aldh on acute DSS-induced colitis, but suggest that in particular EcN aldh may assist recovery from intestinal inflammation.
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Affiliation(s)
| | | | | | | | - Mikael Pedersen
- National Food Institute, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Martin Iain Bahl
- National Food Institute, Technical University of Denmark, Kgs. Lyngby, Denmark
| | | | - Tine Rask Licht
- National Food Institute, Technical University of Denmark, Kgs. Lyngby, Denmark
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Wang Z, Zhou X, Hu X, Zheng C. Quercetin ameliorates Helicobacter pylori-induced gastric epithelial cell injury by regulating specificity protein 1/lipocalin 2 axis in gastritis. J Appl Toxicol 2024; 44:641-650. [PMID: 38056887 DOI: 10.1002/jat.4566] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/03/2023] [Accepted: 11/04/2023] [Indexed: 12/08/2023]
Abstract
Helicobacter pylori (HP) infection is the main cause of most cases of gastritis. Quercetin has been shown to have anti-inflammatory, anti-bacterial, and antiviral activities and has been demonstrated to be involved in HP-induced gastric mucosa injury. Moreover, the secretory protein lipocalin-2 (LCN2) was elevated in HP-infected gastric mucosa. Thus, this work aimed to study the interaction between quercetin and LCN2 in HP-triggered gastric injury during gastritis. Human gastric epithelial cell line GES-1 cells were exposed to HP for functional experiments. Cell viability, apoptosis, and inflammation were evaluated by cell counting kit-8, flow cytometry, and enzyme-linked immunosorbent assay, respectively. Levels of genes and proteins were tested using quantitative reverse transcription polymerase chain reaction and western blotting analyses. The interaction between LCN2 and specificity protein 1 (SP1) was validated using chromatin immunoprecipitation assay and dual-luciferase reporter assay. Thereafter, we found quercetin treatment suppressed HP-induced GES-1 cell apoptotic and inflammatory injury and macrophage M1 polarization. LCN2 was highly expressed in HP-infected gastritis patients and HP-infected GES-1 cells, while quercetin reduced LCN2 expression in HP-infected GES-1 cells; moreover, LCN2 knockdown reversed HP-induced GES-1 cell injury and macrophage M1 polarization, and forced expression of LCN2 abolished the protective effects of quercetin on GES-1 cells under HP infection. Mechanistically, SP1 bound to LCN2 promoter and promoted its transcription. Also, SP1 overexpression counteracted the functions of quercetin on HP-stimulated GES-1 cells. In all, quercetin ameliorated HP-induced gastric epithelial cell apoptotic and inflammatory injuries, and macrophage M1 polarization via the SP1/LCN2 axis.
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Affiliation(s)
- Ziwei Wang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinxin Zhou
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xin Hu
- Department of Digestive Endoscopy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Congru Zheng
- Department of Digestive Endoscopy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Akaraphanth M, Nordgren TM, Gries CM. CXCR2 perturbation promotes Staphylococcus aureus implant-associated infection. J Med Microbiol 2024; 73:001821. [PMID: 38567642 PMCID: PMC11084549 DOI: 10.1099/jmm.0.001821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 03/12/2024] [Indexed: 04/04/2024] Open
Abstract
Introduction. Staphylococcus aureus is the leading cause of acute medical implant infections, representing a significant modern medical concern. The success of S. aureus as a pathogen in these cases resides in its arsenal of virulence factors, resistance to multiple antimicrobials, mechanisms of immune modulation, and ability to rapidly form biofilms associated with implant surfaces. S. aureus device-associated, biofilm-mediated infections are often persistent and notoriously difficult to treat, skewing innate immune responses to promote chronic reoccurring infections. While relatively little is known of the role neutrophils play in response to acute S. aureus biofilm infections, these effector cells must be efficiently recruited to sites of infection via directed chemotaxis. Here we investigate the effects of modulating CXC chemokine receptor 2 (CXCR2) activity, predominantly expressed on neutrophils, during S. aureus implant-associated infection.Hypothesis. We hypothesize that modulation of CXCR2 expression and/or signalling activities during S. aureus infection, and thus neutrophil recruitment, extravasation and antimicrobial activity, will affect infection control and bacterial burdens in a mouse model of implant-associated infection.Aim. This investigation aims to elucidate the impact of altered CXCR2 activity during S. aureus biofilm-mediated infection that may help develop a framework for an effective novel strategy to prevent morbidity and mortality associated with implant infections.Methodology. To examine the role of CXCR2 during S. aureus implant infection, we employed a mouse model of indwelling subcutaneous catheter infection using a community-associated methicillin-resistant S. aureus (MRSA) strain. To assess the role of CXCR2 induction or inhibition during infection, treatment groups received daily intraperitoneal doses of either Lipocalin-2 (Lcn2) or AZD5069, respectively. At the end of the study, catheters and surrounding soft tissues were analysed for bacterial burdens and dissemination, and Cxcr2 transcription within the implant-associated tissues was quantified.Results. Mice treated with Lcn2 developed higher bacterial burdens within the soft tissue surrounding the implant site, which was associated with increased Cxcr2 expression. AZD5069 treatment also resulted in increased implant- and tissues-associated bacterial titres, as well as enhanced Cxcr2 expression.Conclusion. Our results demonstrate that CXCR2 plays an essential role in regulating the severity of S. aureus implant-associated infections. Interestingly, however, perturbation of CXCR2 expression or signalling both resulted in enhanced Cxcr2 transcription and elevated implant-associated bacterial burdens. Thus, CXCR2 appears finely tuned to efficiently recruit effector cells and mediate control of S. aureus biofilm-mediated infection.
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Affiliation(s)
- Mike Akaraphanth
- School of Medicine, University of Colorado, Aurora CO 80045, USA
| | - Tara M. Nordgren
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins CO 80523, USA
| | - Casey M. Gries
- Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins CO 80523, USA
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Shi C, Wang C, Fu Z, Liu J, Zhou Y, Cheng B, Zhang C, Li S, Zhang Y. Lipocalin 2 (LCN2) confers acquired resistance to almonertinib in NSCLC through LCN2-MMP-9 signaling pathway. Pharmacol Res 2024; 201:107088. [PMID: 38295916 DOI: 10.1016/j.phrs.2024.107088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 01/25/2024] [Accepted: 01/26/2024] [Indexed: 02/05/2024]
Abstract
Almonertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is highly selective for EGFR-activating mutations as well as the EGFR T790M mutation in patients with advanced non-small cell lung cancer (NSCLC). However, the development of resistance inevitably occurs and poses a major obstacle to the clinical efficacy of almonertinib. Therefore, a clear understanding of the mechanism is of great significance to overcome drug resistance to almonertinib in the future. In this study, NCI-H1975 cell lines resistant to almonertinib (NCI-H1975 AR) were developed by concentration-increasing induction and were employed for clarification of underlying mechanisms of acquired resistance. Through RNA-seq analysis, the HIF-1 and TGF-β signaling pathways were significantly enriched by gene set enrichment analysis. Lipocalin-2 (LCN2), as the core node in these two signaling pathways, were found to be positively correlated to almonertinib-resistance in NSCLC cells. The function of LCN2 in the drug resistance of almonertinib was investigated through knockdown and overexpression assays in vitro and in vivo. Moreover, matrix metalloproteinases-9 (MMP-9) was further identified as a critical downstream effector of LCN2 signaling, which is regulated via the LCN2-MMP-9 axis. Pharmacological inhibition of MMP-9 could overcome resistance to almonertinib, as evidenced in both in vitro and in vivo models. Our findings suggest that LCN2 was a crucial regulator for conferring almonertinib-resistance in NSCLC and demonstrate the potential utility of targeting the LCN2-MMP-9 axis for clinical treatment of almonertinib-resistant lung adenocarcinoma.
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Affiliation(s)
- Chen Shi
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Cong Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiwen Fu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinmei Liu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuanfeng Zhou
- Department of Preclinical Translational Science, Shanghai Hansoh Biomedical Co.,Ltd., Shanghai 201203. China
| | - Bao Cheng
- Department of Chemistry, Shanghai Hansoh Biomedical Co., Ltd, Shanghai 201203, China
| | - Cong Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shijun Li
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China.
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Konrad ER, Soo J, Conroy AL, Namasopo S, Opoka RO, Hawkes MT. Circulating markers of neutrophil activation and lung injury in pediatric pneumonia in low-resource settings. Pathog Glob Health 2023; 117:708-716. [PMID: 36562081 PMCID: PMC10614712 DOI: 10.1080/20477724.2022.2160885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Diagnostic biomarkers for childhood pneumonia could guide management and improve antibiotic stewardship in low-resource settings where chest x-ray (CXR) is not always available. In this cross-sectional study, we measured chitinase 3-like protein 1 (CHI3L1), surfactant protein D (SP-D), lipocalin-2 (LCN2), and tissue inhibitor of metalloproteinases-1 (TIMP-1) in Ugandan children under the age of five hospitalized with acute lower respiratory tract infection. We determined the association between biomarker levels and primary end-point pneumonia, indicated by CXR consolidation. We included 89 children (median age 11 months, 39% female). Primary endpoint pneumonia was present in 22 (25%). Clinical signs were similar in children with and without CXR consolidation. Broad-spectrum antibiotics (ceftriaxone) were administered in 83 (93%). Levels of CHI3L1, SP-D, LCN2 and TIMP-1 were higher in patients with primary end-point pneumonia compared to patients with normal CXR or other infiltrates. All markers were moderately accurate predictors of primary end-point pneumonia, with area under receiver operator characteristic curves of 0.66-0.70 (p<0.05 for all markers). The probability of CXR consolidation increased monotonically with the number of markers above cut-off. Among 28 patients (31%) in whom all four markers were below the cut-off, the likelihood ratio of CXR consolidation was 0.11 (95%CI 0.015 to 0.73). CHI3L1, SP-D, LCN2 and TIMP-1 were associated with CXR consolidation in children with clinical pneumonia in a low-resource setting. Combinations of quantitative biomarkers may be useful to safely withhold antibiotics in children with a low probability of bacterial infection.
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Affiliation(s)
- Emily R. Konrad
- Department of Pediatrics, University of Alberta, Edmonton, Canada
| | - Jeremy Soo
- Department of Pediatrics, University of Alberta, Edmonton, Canada
| | - Andrea L. Conroy
- Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University School of Medicine, Indianapolis, USA
| | - Sophie Namasopo
- Department of Pediatrics, Kabale District Hospital, Kabale, Uganda
| | - Robert O. Opoka
- Department of Paediatrics and Child Health, Mulago Hospital and Makerere University, Kampala, Uganda
| | - Michael T. Hawkes
- Department of Pediatrics, University of Alberta, Edmonton, Canada
- School of Public Health, University of Alberta, Edmonton, Canada
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada
- Distinguished Researcher, Stollery Science Lab, Edmonton, Canada
- Member, Women and Children’s Health Research Institute, Edmonton, Canada
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Saenz-Pipaon G, Jover E, van der Bent ML, Orbe J, Rodriguez JA, Fernández-Celis A, Quax PHA, Paramo JA, López-Andrés N, Martín-Ventura JL, Nossent AY, Roncal C. Role of LCN2 in a murine model of hindlimb ischemia and in peripheral artery disease patients, and its potential regulation by miR-138-5P. Atherosclerosis 2023; 385:117343. [PMID: 37871404 DOI: 10.1016/j.atherosclerosis.2023.117343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 08/07/2023] [Accepted: 10/10/2023] [Indexed: 10/25/2023]
Abstract
BACKGROUND AND AIMS Peripheral arterial disease (PAD) is a leading cause of morbimortality worldwide. Lipocalin-2 (LCN2) has been associated with higher risk of amputation or mortality in PAD and might be involved in muscle regeneration. Our aim is to unravel the role of LCN2 in skeletal muscle repair and PAD. METHODS AND RESULTS WT and Lcn2-/- mice underwent hindlimb ischemia. Blood and crural muscles were analyzed at the inflammatory and regenerative phases. At day 2, Lcn2-/- male mice, but not females, showed increased blood and soleus muscle neutrophils, and elevated circulating pro-inflammatory monocytes (p < 0.05), while locally, total infiltrating macrophages were reduced (p < 0.05). Moreover, Lcn2-/- soleus displayed an elevation of Cxcl1 (p < 0.001), and Cxcr2 (p < 0.01 in males), and a decrease in Ccl5 (p < 0.05). At day 15, Lcn2 deficiency delayed muscle recovery, with higher density of regenerating myocytes (p < 0.04) and arterioles (αSMA+, p < 0.025). Reverse target prediction analysis identified miR-138-5p as a potential regulator of LCN2, showing an inverse correlation with Lcn2 mRNA in skeletal muscles (rho = -0.58, p < 0.01). In vitro, miR-138-5p mimic reduced Lcn2 expression and luciferase activity in murine macrophages (p < 0.05). Finally, in human serum miR-138-5p was inversely correlated with LCN2 (p ≤ 0.001 adjusted, n = 318), and associated with PAD (Odds ratio 0.634, p = 0.02, adjusted, PAD n = 264, control n = 54). CONCLUSIONS This study suggests a possible dual role of LCN2 in acute and chronic conditions, with a probable role in restraining inflammation early after skeletal muscle ischemia, while being associated with vascular damage in PAD, and identifies miR-138-5p as one potential post-transcriptional regulator of LCN2.
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Affiliation(s)
- Goren Saenz-Pipaon
- Laboratory of Atherothrombosis, Cima Universidad de Navarra, Pamplona, Spain; IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | - Eva Jover
- IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain; Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Pamplona, Spain
| | - M Leontien van der Bent
- Department of Vascular Surgery, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Josune Orbe
- Laboratory of Atherothrombosis, Cima Universidad de Navarra, Pamplona, Spain; IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain; RICORS-ICTUS, ISCIII, Madrid, Spain
| | - Jose A Rodriguez
- Laboratory of Atherothrombosis, Cima Universidad de Navarra, Pamplona, Spain; IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain; CIBERCV, ISCIII, Madrid, Spain
| | - Amaya Fernández-Celis
- IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain; Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Pamplona, Spain
| | - Paul H A Quax
- Department of Vascular Surgery, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Jose A Paramo
- Laboratory of Atherothrombosis, Cima Universidad de Navarra, Pamplona, Spain; IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain; CIBERCV, ISCIII, Madrid, Spain; Hematology Service, Clínica Universidad de Navarra, Pamplona, Spain
| | - Natalia López-Andrés
- IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain; Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Pamplona, Spain
| | | | - Anne Yaël Nossent
- Department of Vascular Surgery, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Carmen Roncal
- Laboratory of Atherothrombosis, Cima Universidad de Navarra, Pamplona, Spain; IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain; CIBERCV, ISCIII, Madrid, Spain.
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Stefanache A, Lungu II, Butnariu IA, Calin G, Gutu C, Marcu C, Grierosu C, Bogdan Goroftei ER, Duceac LD, Dabija MG, Popa F, Damir D. Understanding How Minerals Contribute to Optimal Immune Function. J Immunol Res 2023; 2023:3355733. [PMID: 37946846 PMCID: PMC10632063 DOI: 10.1155/2023/3355733] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 08/16/2023] [Accepted: 09/09/2023] [Indexed: 11/12/2023] Open
Abstract
Sufficient mineral supply is vital not only for the innate immune system but also for the components of the adaptive immune defense, which encompass defense mechanisms against pathogens and the delicate balance of pro- and anti-inflammatory regulation in the long term. Generally, a well-balanced diet is capable of providing the necessary minerals to support the immune system. Nevertheless, specific vulnerable populations should be cautious about obtaining adequate amounts of minerals such as magnesium, zinc, copper, iron, and selenium. Inadequate levels of these minerals can temporarily impair immune competence and disrupt the long-term regulation of systemic inflammation. Therefore, comprehending the mechanisms and sources of these minerals is crucial. In exceptional circumstances, mineral deficiencies may necessitate supplementation; however, excessive intake of supplements can have adverse effects on the immune system and should be avoided. Consequently, any supplementation should be approved by medical professionals and administered in recommended doses. This review emphasizes the crucial significance of minerals in promoting optimal functioning of the immune system. It investigates the indispensable minerals required for immune system function and the regulation of inflammation. Moreover, it delves into the significance of maintaining an optimized intake of minerals from a nutritional standpoint.
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Affiliation(s)
- Alina Stefanache
- “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Ionut-Iulian Lungu
- “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | | | - Gabriela Calin
- Faculty of Dental Medicine, “Apollonia” University of Iasi, 11 Pacurari Street, Iasi 700511, Romania
| | - Cristian Gutu
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | - Constantin Marcu
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | - Carmen Grierosu
- Faculty of Dental Medicine, “Apollonia” University of Iasi, 11 Pacurari Street, Iasi 700511, Romania
| | | | - Letitia-Doina Duceac
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | | | - Florina Popa
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | - Daniela Damir
- “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
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Chakraborty J, Roy S, Pandey P, Mohanty S, Tandon R, Ghosh S. Macrophage plasticity and differentiation on the decellularized human cornea. JOURNAL OF MATERIALS RESEARCH 2023; 38:4625-4640. [DOI: 10.1557/s43578-023-01182-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 09/27/2023] [Indexed: 01/04/2025]
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Živalj M, Van Ginderachter JA, Stijlemans B. Lipocalin-2: A Nurturer of Tumor Progression and a Novel Candidate for Targeted Cancer Therapy. Cancers (Basel) 2023; 15:5159. [PMID: 37958332 PMCID: PMC10648573 DOI: 10.3390/cancers15215159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Within the tumor microenvironment (TME) exists a complex signaling network between cancer cells and stromal cells, which determines the fate of tumor progression. Hence, interfering with this signaling network forms the basis for cancer therapy. Yet, many types of cancer, in particular, solid tumors, are refractory to the currently used treatments, so there is an urgent need for novel molecular targets that could improve current anti-cancer therapeutic strategies. Lipocalin-2 (Lcn-2), a secreted siderophore-binding glycoprotein that regulates iron homeostasis, is highly upregulated in various cancer types. Due to its pleiotropic role in the crosstalk between cancer cells and stromal cells, favoring tumor progression, it could be considered as a novel biomarker for prognostic and therapeutic purposes. However, the exact signaling route by which Lcn-2 promotes tumorigenesis remains unknown, and Lcn-2-targeting moieties are largely uninvestigated. This review will (i) provide an overview on the role of Lcn-2 in orchestrating the TME at the level of iron homeostasis, macrophage polarization, extracellular matrix remodeling, and cell migration and survival, and (ii) discuss the potential of Lcn-2 as a promising novel drug target that should be pursued in future translational research.
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Affiliation(s)
- Maida Živalj
- Brussels Center for Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
- Myeloid Cell Immunology Laboratory, VIB Center for Inflammation Research, 1050 Brussels, Belgium
| | - Jo A. Van Ginderachter
- Brussels Center for Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
- Myeloid Cell Immunology Laboratory, VIB Center for Inflammation Research, 1050 Brussels, Belgium
| | - Benoit Stijlemans
- Brussels Center for Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
- Myeloid Cell Immunology Laboratory, VIB Center for Inflammation Research, 1050 Brussels, Belgium
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Galaris A, Fanidis D, Tsitoura E, Kanellopoulou P, Barbayianni I, Ntatsoulis K, Touloumi K, Gramenoudi S, Karampitsakos T, Tzouvelekis A, Antoniou K, Aidinis V. Increased lipocalin-2 expression in pulmonary inflammation and fibrosis. Front Med (Lausanne) 2023; 10:1195501. [PMID: 37746070 PMCID: PMC10513431 DOI: 10.3389/fmed.2023.1195501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 08/07/2023] [Indexed: 09/26/2023] Open
Abstract
Introduction Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive interstitial lung disease with dismal prognosis. The underlying pathogenic mechanisms are poorly understood, resulting in a lack of effective treatments. However, recurrent epithelial damage is considered critical for disease initiation and perpetuation, via the secretion of soluble factors that amplify inflammation and lead to fibroblast activation and exuberant deposition of ECM components. Lipocalin-2 (LCN2) is a neutrophil gelatinase-associated lipocalin (NGAL) that has been suggested as a biomarker of kidney damage. LCN2 has been reported to modulate innate immunity, including the recruitment of neutrophils, and to protect against bacterial infections by sequestering iron. Methods In silico analysis of publicly available transcriptomic datasets; ELISAs on human IPF patients' bronchoalveolar lavage fluids (BALFs); bleomycin (BLM)-induced pulmonary inflammation and fibrosis and LPS-induced acute lung injury (ALI) in mice: pulmonary function tests, histology, Q-RT-PCR, western blot, and FACS analysis. Results and discussion Increased LCN2 mRNA expression was detected in the lung tissue of IPF patients negatively correlating with respiratory functions, as also shown for BALF LCN2 protein levels in a cohort of IPF patients. Increased Lcn2 expression was also detected upon BLM-induced pulmonary inflammation and fibrosis, especially at the acute phase correlating with neutrophilic infiltration, as well as upon LPS-induced ALI, an animal model characterized by neutrophilic infiltration. Surprisingly, and non withstanding the limitations of the study and the observed trends, Lcn2-/- mice were found to still develop BLM- or LPS-induced pulmonary inflammation and fibrosis, thus questioning a major pathogenic role for Lcn2 in mice. However, LCN2 qualifies as a surrogate biomarker of pulmonary inflammation and a possible indicator of compromised pulmonary functions, urging for larger studies.
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Affiliation(s)
- Apostolos Galaris
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Dionysios Fanidis
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Eliza Tsitoura
- Department of Respiratory Medicine, School of Medicine, University of Crete, Heraklion, Greece
| | - Paraskevi Kanellopoulou
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Ilianna Barbayianni
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Konstantinos Ntatsoulis
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Katerina Touloumi
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Sofia Gramenoudi
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Theodoros Karampitsakos
- Department of Respiratory Medicine, School of Medicine, University of Patras, Patras, Greece
| | - Argyrios Tzouvelekis
- Department of Respiratory Medicine, School of Medicine, University of Patras, Patras, Greece
| | - Katerina Antoniou
- Department of Respiratory Medicine, School of Medicine, University of Crete, Heraklion, Greece
| | - Vassilis Aidinis
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
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An HS, Lee J, Lee SJ, Jeong EA, Shin HJ, Kim KE, Roh GS. Lipocalin-2 deletion attenuates lipopolysaccharide-induced acute lung inflammation via downregulating chemotaxis-related genes. Biochem Biophys Res Commun 2023; 652:14-21. [PMID: 36806084 DOI: 10.1016/j.bbrc.2023.02.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 02/12/2023] [Indexed: 02/18/2023]
Abstract
Lipocalin-2 (LCN2) is an acute phase protein used as a biomarker for acute lung injury (ALI). Although the innate immune functions of LCN2 have been studied, how LCN2 contributes to ALI induced by lipopolysaccharide (LPS) remains unknown. In this study, we investigated the effect of LCN2 deletion on LPS-induced ALI using RNA-sequencing. LPS-treated LCN2 knockout (KO) mice had a decreased histopathological score and reduced neutrophil and macrophage infiltration in lung tissue compared with LPS-treated WT mice. RNA-sequencing analysis identified 38 differentially expressed genes (DEGs), including Cxcl5, Cxcl13, Xcl1, Saa1, and Cd14. In particular, Gene Ontology analysis of DEGs revealed a significant reduction in the inflammatory response, neutrophil chemotaxis, and chemokine-mediated signaling in LPS-treated LCN2KO mice compared with LPS-treated WT mice. Thus, these results suggest that LCN2 deletion alleviates LPS-induced ALI and that LCN2 may be involved in chemotaxis-related gene expression.
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Affiliation(s)
- Hyeong Seok An
- Department of Anatomy & Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Jaewoong Lee
- Department of Anatomy & Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - So Jeong Lee
- Department of Anatomy & Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Eun Ae Jeong
- Department of Anatomy & Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Hyun Joo Shin
- Department of Anatomy & Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Kyung Eun Kim
- Department of Anatomy & Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Gu Seob Roh
- Department of Anatomy & Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea.
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Zhao RY, Wei PJ, Sun X, Zhang DH, He QY, Liu J, Chang JL, Yang Y, Guo ZN. Role of lipocalin 2 in stroke. Neurobiol Dis 2023; 179:106044. [PMID: 36804285 DOI: 10.1016/j.nbd.2023.106044] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 01/22/2023] [Accepted: 02/12/2023] [Indexed: 02/18/2023] Open
Abstract
Stroke is the second leading cause of death worldwide; however, the treatment choices available to neurologists are limited in clinical practice. Lipocalin 2 (LCN2) is a secreted protein, belonging to the lipocalin superfamily, with multiple biological functions in mediating innate immune response, inflammatory response, iron-homeostasis, cell migration and differentiation, energy metabolism, and other processes in the body. LCN2 is expressed at low levels in the brain under normal physiological conditions, but its expression is significantly up-regulated in multiple acute stimulations and chronic pathologies. An up-regulation of LCN2 has been found in the blood/cerebrospinal fluid of patients with ischemic/hemorrhagic stroke, and could serve as a potential biomarker for the prediction of the severity of acute stroke. LCN2 activates reactive astrocytes and microglia, promotes neutrophil infiltration, amplifies post-stroke inflammation, promotes blood-brain barrier disruption, white matter injury, and neuronal death. Moreover, LCN2 is involved in brain injury induced by thrombin and erythrocyte lysates, as well as microvascular thrombosis after hemorrhage. In this paper, we review the role of LCN2 in the pathological processes of ischemic stroke; intracerebral hemorrhage; subarachnoid hemorrhage; and stroke-related brain diseases, such as vascular dementia and post-stroke depression, and their underlying mechanisms. We hope that this review will help elucidate the value of LCN2 as a therapeutic target in stroke.
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Affiliation(s)
- Ruo-Yu Zhao
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Chang Chun, China
| | - Peng-Ju Wei
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Xin Sun
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Chang Chun, China
| | - Dian-Hui Zhang
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Chang Chun, China
| | - Qian-Yan He
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Chang Chun, China
| | - Jie Liu
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Chang Chun, China
| | - Jun-Lei Chang
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Yi Yang
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Chang Chun, China; Neuroscience Research Center, the First Hospital of Jilin University, Chang Chun, China; Jilin Provincial Key Laboratory of Cerebrovascular Disease, Changchun, China.
| | - Zhen-Ni Guo
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Chang Chun, China; Neuroscience Research Center, the First Hospital of Jilin University, Chang Chun, China; Jilin Provincial Key Laboratory of Cerebrovascular Disease, Changchun, China.
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15
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Yang HH, Wang X, Li S, Liu Y, Akbar R, Fan GC. Lipocalin family proteins and their diverse roles in cardiovascular disease. Pharmacol Ther 2023; 244:108385. [PMID: 36966973 PMCID: PMC10079643 DOI: 10.1016/j.pharmthera.2023.108385] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 03/01/2023] [Accepted: 03/13/2023] [Indexed: 04/03/2023]
Abstract
The lipocalin (LCN) family members, a group of small extracellular proteins with 160-180 amino acids in length, can be detected in all kingdoms of life from bacteria to human beings. They are characterized by low similarity of amino acid sequence but highly conserved tertiary structures with an eight-stranded antiparallel β-barrel which forms a cup-shaped ligand binding pocket. In addition to bind small hydrophobic ligands (i.e., fatty acids, odorants, retinoids, and steroids) and transport them to specific cells, lipocalins (LCNs) can interact with specific cell membrane receptors to activate their downstream signaling pathways, and with soluble macromolecules to form the complex. Consequently, LCNs exhibit great functional diversity. Accumulating evidence has demonstrated that LCN family proteins exert multiple layers of function in the regulation of many physiological processes and human diseases (i.e., cancers, immune disorders, metabolic disease, neurological/psychiatric disorders, and cardiovascular disease). In this review, we firstly introduce the structural and sequence properties of LCNs. Next, six LCNs including apolipoprotein D (ApoD), ApoM, lipocalin 2 (LCN2), LCN10, retinol-binding protein 4 (RBP4), and Lipocalin-type prostaglandin D synthase (L-PGDS) which have been characterized so far are highlighted for their diagnostic/prognostic values and their potential effects on coronary artery disease and myocardial infarction injury. The roles of these 6 LCNs in cardiac hypertrophy, heart failure, diabetes-induced cardiac disorder, and septic cardiomyopathy are also summarized. Finally, their therapeutic potential for cardiovascular disease is discussed in each section.
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Affiliation(s)
- Hui-Hui Yang
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Xiaohong Wang
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Siru Li
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Yueying Liu
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Rubab Akbar
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Guo-Chang Fan
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
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Wang D, Li X, Jiao D, Cai Y, Qian L, Shen Y, Lu Y, Zhou Y, Fu B, Sun R, Tian Z, Zheng X, Wei H. LCN2 secreted by tissue-infiltrating neutrophils induces the ferroptosis and wasting of adipose and muscle tissues in lung cancer cachexia. J Hematol Oncol 2023; 16:30. [PMID: 36973755 PMCID: PMC10044814 DOI: 10.1186/s13045-023-01429-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 03/19/2023] [Indexed: 03/29/2023] Open
Abstract
BACKGROUND Cancer cachexia is a deadly wasting syndrome that accompanies various diseases (including ~ 50% of cancers). Clinical studies have established that cachexia is not a nutritional deficiency and is linked to expression of certain proteins (e.g., interleukin-6 and C-reactive protein), but much remains unknown about this often fatal syndrome. METHODS First, cachexia was created in experimental mouse models of lung cancer. Samples of human lung cancer were used to identify the association between the serum lipocalin 2 (LCN2) level and cachexia progression. Then, mouse models with LCN2 blockade or LCN2 overexpression were used to ascertain the role of LCN2 upon ferroptosis and cachexia. Furthermore, antibody depletion of tissue-infiltrating neutrophils (TI-Neu), as well as myeloid-specific-knockout of Lcn2, were undertaken to reveal if LCN2 secreted by TI-Neu caused cachexia. Finally, chemical inhibition of ferroptosis was conducted to illustrate the effect of ferroptosis upon tissue wasting. RESULTS Protein expression of LCN2 was higher in the wasting adipose tissue and muscle tissues of experimental mouse models of lung cancer cachexia. Moreover, evaluation of lung cancer patients revealed an association between the serum LCN2 level and cachexia progression. Inhibition of LCN2 expression reduced cachexia symptoms significantly and inhibited tissue wasting in vivo. Strikingly, we discovered a significant increase in the number of TI-Neu in wasting tissues, and that these innate immune cells secreted high levels of LCN2. Antibody depletion of TI-Neu, as well as myeloid-specific-knockout of Lcn2, prevented ferroptosis and tissue wasting in experimental models of lung cancer cachexia. Chemical inhibition of ferroptosis alleviated tissue wasting significantly and also prolonged the survival of cachectic mice. CONCLUSIONS Our study provides new insights into how LCN2-induced ferroptosis functionally impacts tissue wasting. We identified LCN2 as a potential target in the treatment of cancer cachexia.
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Affiliation(s)
- Dong Wang
- Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China
- CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- Institue of Immunology, University of Science and Technology of China, Hefei, 230027, Anhui, China
| | - Xiaohui Li
- CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- Institue of Immunology, University of Science and Technology of China, Hefei, 230027, Anhui, China
| | - Defeng Jiao
- CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- Institue of Immunology, University of Science and Technology of China, Hefei, 230027, Anhui, China
| | - Ying Cai
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230031, Anhui, China
| | - Liting Qian
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230031, Anhui, China
| | - Yiqing Shen
- CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- Institue of Immunology, University of Science and Technology of China, Hefei, 230027, Anhui, China
| | - Yichen Lu
- CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- Institue of Immunology, University of Science and Technology of China, Hefei, 230027, Anhui, China
| | - Yonggang Zhou
- CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- Institue of Immunology, University of Science and Technology of China, Hefei, 230027, Anhui, China
| | - Binqing Fu
- CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- Institue of Immunology, University of Science and Technology of China, Hefei, 230027, Anhui, China
| | - Rui Sun
- CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- Institue of Immunology, University of Science and Technology of China, Hefei, 230027, Anhui, China
| | - Zhigang Tian
- CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- Institue of Immunology, University of Science and Technology of China, Hefei, 230027, Anhui, China
| | - Xiaohu Zheng
- Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China.
- CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- Institue of Immunology, University of Science and Technology of China, Hefei, 230027, Anhui, China.
| | - Haiming Wei
- Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China.
- CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- Institue of Immunology, University of Science and Technology of China, Hefei, 230027, Anhui, China.
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The von Hippel-Lindau Tumor Suppressor Gene Mutations Modulate Lipocalin-2 Expression in Ferroptotic-Inflammatory Pathways. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:7736638. [PMID: 36718277 PMCID: PMC9884170 DOI: 10.1155/2023/7736638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/26/2022] [Accepted: 11/24/2022] [Indexed: 01/22/2023]
Abstract
A previous study of an animal model with tumor suppressor gene von Hippel-Lindau (VHL) conditional knockdown suggested that tissue inflammation and fibrosis play important roles in the development of clear-cell renal cell carcinoma (ccRCC), which is consistent with the epidemiological evidence linking inflammatory kidney disease and renal cancer. Ferroptosis and inflammation have been linked in a recent study, but the exact mechanism remains unclear. This study is aimed at investigating the mechanism of lipocalin-2- (LCN-2-) mediated ferroptosis and inflammation in vhl-mutated HK-2 cells and mouse primary proximal tubule cells (mRTCs) and the polarization of macrophage RAW 264.7 cells. Based on the levels of lipid reactive oxygen species (ROS) and the expression of glutathione peroxidase 4 (GPX4) in HK-2 cells, we observed that a VHL mutation increased ROS production and depressed GPX4 expression, whereas LCN-2 knockdown reversed these effects. Accordingly, VHL appears to affect ferroptosis in an LCN-2-dependent manner. We also revealed that LCN-2 sensitizes HK-2 cells to inflammation and macrophage RAW 264.7 cells to M1-like polarization. This study provides novel insights into the potential therapeutic target and strategy for attenuating the progression of ccRCC by revealing the role of VHL in regulating chronic inflammation within the LCN-2-ferroptosis pathway.
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18
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An HS, Yoo JW, Jeong JH, Heo M, Hwang SH, Jang HM, Jeong EA, Lee J, Shin HJ, Kim KE, Shin MC, Roh GS. Lipocalin-2 promotes acute lung inflammation and oxidative stress by enhancing macrophage iron accumulation. Int J Biol Sci 2023; 19:1163-1177. [PMID: 36923935 PMCID: PMC10008694 DOI: 10.7150/ijbs.79915] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 01/30/2023] [Indexed: 03/14/2023] Open
Abstract
Lipocalin-2 (LCN2) is an acute-phase protein that regulates inflammatory responses to bacteria or lipopolysaccharide (LPS). Although the bacteriostatic role of LCN2 is well studied, the function of LCN2 in acute lung damage remains unclear. Here, LCN2 knockout (KO) mice were used to investigate the role of LCN2 in LPS-treated mice with or without recombinant LCN2 (rLCN2). In addition, we employed patients with pneumonia. RAW264.7 cells were given LCN2 inhibition or rLCN2 with or without iron chelator deferiprone. LCN2 KO mice had a higher survival rate than wild-type (WT) mice after LPS treatment. In addition to elevated LCN2 levels in serum and bronchoalveolar lavage fluid (BALF), LPS treatment also increased LCN2 protein in alveolar macrophage lysates of BALF. LCN2 deletion attenuated neutrophil and macrophage infiltration in the lungs of LPS-treated mice as well as serum and BALF interleukin-6 (IL-6). Circulating proinflammatory cytokines and LCN2-positive macrophages were prominently increased in the BALF of pneumonia patients. In addition to increase of iron-stained macrophages in pneumonia patients, increased iron-stained macrophages and oxidative stress in LPS-treated mice were inhibited by LCN2 deletion. In contrast, rLCN2 pretreatment aggravated lung inflammation and oxidative stress in LPS-treated WT mice and then resulted in higher mortality. In RAW264.7 cells, exogenous LCN2 treatment also increased inflammation and oxidative stress, whereas LCN2 knockdown markedly diminished these effects. Furthermore, deferiprone inhibited inflammation, oxidative stress, and phagocytosis in RAW264.7 cells with high LCN2 levels, as well as LPS-induced acute lung injury in WT and LCN2 KO mice. Thus, these findings suggest that LCN2 plays a key role in inflammation and oxidative stress following acute lung injury and that LCN2 is a potential therapeutic target for pneumonia or acute lung injury.
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Affiliation(s)
- Hyeong Seok An
- Department of Anatomy & Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Jung-Wan Yoo
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Gyeongsang National University Hospital, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Jong Hwan Jeong
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Gyeongsang National University Hospital, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Manbong Heo
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Gyeongsang National University Hospital, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Si Hwan Hwang
- Department of Medicine, College of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Hye Min Jang
- Department of Anatomy & Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Eun Ae Jeong
- Department of Anatomy & Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Jaewoong Lee
- Department of Anatomy & Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Hyun Joo Shin
- Department of Anatomy & Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Kyung Eun Kim
- Department of Anatomy & Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea
| | - Meong Cheol Shin
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Gu Seob Roh
- Department of Anatomy & Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea
- ✉ Corresponding author: Gu Seob Roh, M.D., Ph.D. Department of Anatomy, College of Medicine, Gyeongsang National University, 15, 816 Beon-gil, Jinju-daero, Jinju, Gyeongnam 52727, Republic of Korea. Tel: +82-55-772-8035, E-mail:
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Dufrusine B, Valentinuzzi S, Bibbò S, Damiani V, Lanuti P, Pieragostino D, Del Boccio P, D’Alessandro E, Rabottini A, Berghella A, Allocati N, Falasca K, Ucciferri C, Mucedola F, Di Perna M, Martino L, Vecchiet J, De Laurenzi V, Dainese E. Iron Dyshomeostasis in COVID-19: Biomarkers Reveal a Functional Link to 5-Lipoxygenase Activation. Int J Mol Sci 2022; 24:15. [PMID: 36613462 PMCID: PMC9819889 DOI: 10.3390/ijms24010015] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) is characterized by a broad spectrum of clinical symptoms. After acute infection, some subjects develop a post-COVID-19 syndrome known as long-COVID. This study aims to recognize the molecular and functional mechanisms that occur in COVID-19 and long-COVID patients and identify useful biomarkers for the management of patients with COVID-19 and long-COVID. Here, we profiled the response to COVID-19 by performing a proteomic analysis of lymphocytes isolated from patients. We identified significant changes in proteins involved in iron metabolism using different biochemical analyses, considering ceruloplasmin (Cp), transferrin (Tf), hemopexin (HPX), lipocalin 2 (LCN2), and superoxide dismutase 1 (SOD1). Moreover, our results show an activation of 5-lipoxygenase (5-LOX) in COVID-19 and in long-COVID possibly through an iron-dependent post-translational mechanism. Furthermore, this work defines leukotriene B4 (LTB4) and lipocalin 2 (LCN2) as possible markers of COVID-19 and long-COVID and suggests novel opportunities for prevention and treatment.
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Affiliation(s)
- Beatrice Dufrusine
- Department of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, 64100 Teramo, Italy
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Silvia Valentinuzzi
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Sandra Bibbò
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Verena Damiani
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Paola Lanuti
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Department of Medicine and Aging Science, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | - Damiana Pieragostino
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Piero Del Boccio
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Ersilia D’Alessandro
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Alberto Rabottini
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Alessandro Berghella
- Department of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, 64100 Teramo, Italy
| | - Nerino Allocati
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Katia Falasca
- Department of Medicine and Aging Science, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
- Clinic of Infectious Diseases, S.S. Annunziata Hospital, 66100 Chieti, Italy
| | - Claudio Ucciferri
- Clinic of Infectious Diseases, S.S. Annunziata Hospital, 66100 Chieti, Italy
| | - Francesco Mucedola
- Clinic of Infectious Diseases, S.S. Annunziata Hospital, 66100 Chieti, Italy
| | - Marco Di Perna
- Pneumology Department, “SS Annunziata” Hospital, 66100 Chieti, Italy
| | - Laura Martino
- Pneumology Department, “SS Annunziata” Hospital, 66100 Chieti, Italy
| | - Jacopo Vecchiet
- Department of Medicine and Aging Science, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
- Clinic of Infectious Diseases, S.S. Annunziata Hospital, 66100 Chieti, Italy
| | - Vincenzo De Laurenzi
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Enrico Dainese
- Department of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, 64100 Teramo, Italy
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20
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Indino S, Borzi C, Moscheni C, Sartori P, De Cecco L, Bernardo G, Le Noci V, Arnaboldi F, Triulzi T, Sozzi G, Tagliabue E, Sfondrini L, Gagliano N, Moro M, Sommariva M. The Educational Program of Macrophages toward a Hyperprogressive Disease-Related Phenotype Is Orchestrated by Tumor-Derived Extracellular Vesicles. Int J Mol Sci 2022; 23:ijms232415802. [PMID: 36555441 PMCID: PMC9779478 DOI: 10.3390/ijms232415802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 12/03/2022] [Accepted: 12/09/2022] [Indexed: 12/14/2022] Open
Abstract
Hyperprogressive disease (HPD), an aggressive acceleration of tumor growth, was observed in a group of cancer patients treated with anti-PD1/PDL1 antibodies. The presence of a peculiar macrophage subset in the tumor microenvironment is reported to be a sort of "immunological prerequisite" for HPD development. These macrophages possess a unique phenotype that it is not clear how they acquire. We hypothesized that certain malignant cells may promote the induction of an "HPD-related" phenotype in macrophages. Bone-marrow-derived macrophages were exposed to the conditioned medium of five non-small cell lung cancer cell lines. Macrophage phenotype was analyzed by microarray gene expression profile and real-time PCR. We found that human NSCLC cell lines, reported as undergoing HPD-like tumor growth in immunodeficient mice, polarized macrophages towards a peculiar pro-inflammatory phenotype sharing both M1 and M2 features. Lipid-based factors contained in cancer cell-conditioned medium induced the over-expression of several pro-inflammatory cytokines and the activation of innate immune receptor signaling pathways. We also determined that tumor-derived Extracellular Vesicles represent the main components involved in the observed macrophage re-education program. The present study might represent the starting point for the future development of diagnostic tools to identify potential hyperprogressors.
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Affiliation(s)
- Serena Indino
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, Italy
| | - Cristina Borzi
- Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Claudia Moscheni
- Dipartimento di Scienze Biomediche e Cliniche, Università degli Studi di Milano, Via G. B. Grassi, 74, L.I.T.A. Vialba, 20157 Milan, Italy
| | - Patrizia Sartori
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, Italy
| | - Loris De Cecco
- Molecular Mechanisms Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy
| | - Giancarla Bernardo
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, Italy
| | - Valentino Le Noci
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, Italy
| | - Francesca Arnaboldi
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, Italy
| | - Tiziana Triulzi
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy
| | - Gabriella Sozzi
- Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Elda Tagliabue
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy
| | - Lucia Sfondrini
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, Italy
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy
| | - Nicoletta Gagliano
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, Italy
| | - Massimo Moro
- Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy
| | - Michele Sommariva
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, Italy
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy
- Correspondence: ; Tel.: +39-0250315401
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21
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Tang J, Suo L, Li F, Yang C, Bian K, Wang Y. ITRAQ-based quantitative proteomics analysis of forest musk deer with pneumonia. Front Vet Sci 2022; 9:1012276. [DOI: 10.3389/fvets.2022.1012276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 10/05/2022] [Indexed: 11/13/2022] Open
Abstract
Pneumonia can seriously threaten the life of forest musk deer (FMD, an endangered species). To gain a comprehensive understanding of pneumonia pathogenesis in FMD, iTRAQ-based proteomics analysis was performed in diseased (Pne group) lung tissues of FMD that died of pneumonia and normal lung tissues (Ctrl group) of FMD that died from fighting against each other. Results showed that 355 proteins were differentially expressed (fold change ≥ 1.2 and adjusted P-value < 0.05) in Pne vs. Ctrl. GO/KEGG annotation and enrichment analyses showed that dysregulated proteins might play vital roles in bacterial infection and immunity. Given the close association between bacterial infection and pneumonia, 32 dysregulated proteins related to Staphylococcus aureus infection, bacterial invasion of epithelial cells, and pathogenic Escherichia coli infection were screened out. Among these 32 proteins, 13 proteins were mapped to the bovine genome. Given the close phylogenetic relationships of FMD and bovine, the protein-protein interaction networks of the above-mentioned 13 proteins were constructed by the String database. Based on the node degree analysis, 5 potential key proteins related to pneumonia-related bacterial infection in FMD were filtered out. Moreover, 85 dysregulated proteins related to the immune system process were identified given the tight connection between immune dysregulation and pneumonia pathogenesis. Additionally, 12 proteins that might function as crucial players in pneumonia-related immune response in FMD were screened out using the same experimental strategies described above. In conclusion, some vital proteins, biological processes, and pathways in pneumonia development were identified in FMD.
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22
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Wu Z, Shao J, Zheng J, Liu B, Li Z, Shen N. A zero-sum game or an interactive frame? Iron competition between bacteria and humans in infection war. Chin Med J (Engl) 2022; 135:1917-1926. [PMID: 35830263 PMCID: PMC9746790 DOI: 10.1097/cm9.0000000000002233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Indexed: 11/26/2022] Open
Abstract
ABSTRACT Iron is an essential trace element for both humans and bacteria. It plays a vital role in life, such as in redox reactions and electron transport. Strict regulatory mechanisms are necessary to maintain iron homeostasis because both excess and insufficient iron are harmful to life. Competition for iron is a war between humans and bacteria. To grow, reproduce, colonize, and successfully cause infection, pathogens have evolved various mechanisms for iron uptake from humans, principally Fe 3+ -siderophore and Fe 2+ -heme transport systems. Humans have many innate immune mechanisms that regulate the distribution of iron and inhibit bacterial iron uptake to help resist bacterial invasion and colonization. Meanwhile, researchers have invented detection test strips and coupled antibiotics with siderophores to create tools that take advantage of this battle for iron, to help eliminate pathogens. In this review, we summarize bacterial and human iron metabolism, competition for iron between humans and bacteria, siderophore sensors, antibiotics coupled with siderophores, and related phenomena. We also discuss how competition for iron can be used for diagnosis and treatment of infection in the future.
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Affiliation(s)
- Zhenchao Wu
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China
- Center for Infectious Diseases, Peking University Third Hospital, Beijing 100191, China
| | - Jiqi Shao
- Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Jiajia Zheng
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Beibei Liu
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Zhiyuan Li
- Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Ning Shen
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China
- Center for Infectious Diseases, Peking University Third Hospital, Beijing 100191, China
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23
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Välikangas T, Junttila S, Rytkönen KT, Kukkonen-Macchi A, Suomi T, Elo LL. COVID-19-specific transcriptomic signature detectable in blood across multiple cohorts. Front Genet 2022; 13:929887. [PMID: 35991542 PMCID: PMC9388772 DOI: 10.3389/fgene.2022.929887] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/27/2022] [Indexed: 01/08/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading across the world despite vast global vaccination efforts. Consequently, many studies have looked for potential human host factors and immune mechanisms associated with the disease. However, most studies have focused on comparing COVID-19 patients to healthy controls, while fewer have elucidated the specific host factors distinguishing COVID-19 from other infections. To discover genes specifically related to COVID-19, we reanalyzed transcriptome data from nine independent cohort studies, covering multiple infections, including COVID-19, influenza, seasonal coronaviruses, and bacterial pneumonia. The identified COVID-19-specific signature consisted of 149 genes, involving many signals previously associated with the disease, such as induction of a strong immunoglobulin response and hemostasis, as well as dysregulation of cell cycle-related processes. Additionally, potential new gene candidates related to COVID-19 were discovered. To facilitate exploration of the signature with respect to disease severity, disease progression, and different cell types, we also offer an online tool for easy visualization of the selected genes across multiple datasets at both bulk and single-cell levels.
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Affiliation(s)
- Tommi Välikangas
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Sini Junttila
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Kalle T. Rytkönen
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Anu Kukkonen-Macchi
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Tomi Suomi
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Laura L. Elo
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
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Grubwieser P, Hoffmann A, Hilbe R, Seifert M, Sonnweber T, Böck N, Theurl I, Weiss G, Nairz M. Airway Epithelial Cells Differentially Adapt Their Iron Metabolism to Infection With Klebsiella pneumoniae and Escherichia coli In Vitro. Front Cell Infect Microbiol 2022; 12:875543. [PMID: 35663465 PMCID: PMC9157649 DOI: 10.3389/fcimb.2022.875543] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/22/2022] [Indexed: 12/13/2022] Open
Abstract
Background Pneumonia is often elicited by bacteria and can be associated with a severe clinical course, respiratory failure and the need for mechanical ventilation. In the alveolus, type-2-alveolar-epithelial-cells (AECII) contribute to innate immune functions. We hypothesized that AECII actively adapt cellular iron homeostasis to restrict this essential nutrient from invading pathogens - a defense strategy termed 'nutritional immunity', hitherto mainly demonstrated for myeloid cells. Methods We established an in-vitro infection model using the human AECII-like cell line A549. We infected cells with Klebsiella pneumoniae (K. pneumoniae) and Escherichia coli (E. coli), two gram-negative bacteria with different modes of infection and frequent causes of hospital-acquired pneumonia. We followed the entry and intracellular growth of these gram-negative bacteria and analyzed differential gene expression and protein levels of key inflammatory and iron metabolism molecules. Results Both, K. pneumoniae and E. coli are able to invade A549 cells, whereas only K. pneumoniae is capable of proliferating intracellularly. After peak bacterial burden, the number of intracellular pathogens declines, suggesting that epithelial cells initiate antimicrobial immune effector pathways to combat bacterial proliferation. The extracellular pathogen E. coli induces an iron retention phenotype in A549 cells, mainly characterized by the downregulation of the pivotal iron exporter ferroportin, the upregulation of the iron importer transferrin-receptor-1 and corresponding induction of the iron storage protein ferritin. In contrast, cells infected with the facultative intracellular bacterium K. pneumoniae exhibit an iron export phenotype indicated by ferroportin upregulation. This differential regulation of iron homeostasis and the pathogen-specific inflammatory reaction is likely mediated by oxidative stress. Conclusion AECII-derived A549 cells show pathogen-specific innate immune functions and adapt their iron handling in response to infection. The differential regulation of iron transporters depends on the preferential intra- or extracellular localization of the pathogen and likely aims at limiting bacterial iron availability.
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Affiliation(s)
- Philipp Grubwieser
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Alexander Hoffmann
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Richard Hilbe
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Markus Seifert
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Thomas Sonnweber
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Nina Böck
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Igor Theurl
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
- Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Manfred Nairz
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
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25
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Huang Z, Li H, Liu S, Jia J, Zheng Y, Cao B. Identification of Neutrophil-Related Factor LCN2 for Predicting Severity of Patients With Influenza A Virus and SARS-CoV-2 Infection. Front Microbiol 2022; 13:854172. [PMID: 35495713 PMCID: PMC9039618 DOI: 10.3389/fmicb.2022.854172] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/14/2022] [Indexed: 01/14/2023] Open
Abstract
Background Influenza and COVID-19 are respiratory infectious diseases that are characterized by high contagiousness and high mutation and pose a serious threat to global health. After Influenza A virus (IAV) and SARS-CoV-2 infection, severe cases may develop into acute lung injury. Immune factors act as an important role during infection and inflammation. However, the molecular immune mechanisms still remain unclear. We aimed to explore immune-related host factors and core biomarker for severe infection, to provide a new therapeutic target of host factor in patients. Methods Gene expression profiles were obtained from Gene Expression Omnibus and the Seurat R package was used for data process of single-cell transcriptome. Differentially expressed gene analysis and cell cluster were used to explore core host genes and source cells of genes. We performed Gene Ontology enrichment, Kyoto Encyclopedia of Genes and Genomes analysis, and gene set enrichment analysis to explore potential biological functions of genes. Gene set variation analysis was used to evaluate the important gene set variation score for different samples. We conduct Enzyme-linked immunosorbent assay (ELISA) to test plasma concentrations of Lipocalin 2 (LCN2). Results Multiple virus-related, cytokine-related, and chemokine-related pathways involved in process of IAV infection and inflammatory response mainly derive from macrophages and neutrophils. LCN2 mainly in neutrophils was significantly upregulated after either IAV or SARS-CoV-2 infection and positively correlated with disease severity. The plasma LCN2 of influenza patients were elevated significantly compared with healthy controls by ELISA and positively correlated with disease severity of influenza patients. Further bioinformatics analysis revealed that LCN2 involved in functions of neutrophils, including neutrophil degranulation, neutrophil activation involved in immune response, and neutrophil extracellular trap formation. Conclusion The neutrophil-related LCN2 could be a promising biomarker for predicting severity of patients with IAV and SARS-CoV-2 infection and may as a new treatment target in severe patients.
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Affiliation(s)
- Zhisheng Huang
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.,Department of Pulmonary and Critical Care Medicine, Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China
| | - Hui Li
- Department of Pulmonary and Critical Care Medicine, Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China
| | - Shuai Liu
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Ju Jia
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.,Department of Pulmonary and Critical Care Medicine, Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China
| | - Ying Zheng
- Department of Pulmonary and Critical Care Medicine, Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.,China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, Clinical Center for Pulmonary Infections, Capital Medical University, Beijing, China
| | - Bin Cao
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.,Department of Pulmonary and Critical Care Medicine, Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.,China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, Clinical Center for Pulmonary Infections, Capital Medical University, Beijing, China
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26
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Abstract
Influenza A virus (IAV), an obligatory intracellular parasite, uses host cellular molecules to complete its replication cycle and suppress immune responses. Proteasome subunit alpha type 2 (PSMA2) is a cellular protein highly expressed in IAV-infected human lung epithelial A549 cells. PSMA2 is part of the 20S proteasome complex that degrades or recycles defective proteins and involves proteolytic modification of many cellular regulatory proteins. However, the role of PSMA2 in IAV replication is not well understood. In this study, PSMA2 knockdown (KD) in A549 cells caused a significant reduction in extracellular progeny IAV, but intracellular viral protein translation and viral RNA transcription were not affected. This indicates that PSMA2 is a critical host factor for IAV maturation. To better understand the interplay between PSMA2 KD and IAV infection at the proteomic level, we used the SomaScan 1.3K version, which measures 1,307 proteins to analyze alterations induced by these treatments. We found seven cellular signaling pathways, including phospholipase C signaling, Pak signaling, and nuclear factor erythroid 2p45-related factor 2 (NRF2)-mediated oxidative stress response signaling, that were inhibited by IAV infection but significantly activated by PSMA2 KD. Further analysis of NRF2-mediated oxidative stress response signaling indicated IAV inhibits accumulation of reactive oxygen species (ROS), but ROS levels significantly increased during IAV infection in PSMA2 KD cells. However, IAV infection caused significantly higher NFR2 nuclear translocation that was inhibited in PSMA2 KD cells. This indicates that PSMA2 is required for NRF2-mediated ROS neutralization and that IAV uses PSMA2 to escape viral clearance via the NRF2-mediated cellular oxidative response. IMPORTANCE Influenza A virus (IAV) remains one of the most significant infectious agents, responsible for 3 million to 5 million illnesses each year and more than 50 million deaths during the 20th century. The cellular processes that promote and inhibit IAV infection and pathogenesis remain only partially understood. PSMA2 is a critical component of the 20S proteasome and ubiquitin-proteasome system, which is important in the replication of numerous viruses. This study examined host protein responses to IAV infection alone, PSMA2 knockdown alone, and IAV infection in the presence of PSMA2 knockdown and determined that interfering with PSMA2 function affected IAV maturation. These results help us better understand the importance of PSMA2 in IAV replication and may pave the way for designing additional IAV antivirals targeting PSMA2 or the host proteasome for the treatment of seasonal flu.
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Gorki AD, Symmank D, Zahalka S, Lakovits K, Hladik A, Langer B, Maurer B, Sexl V, Kain R, Knapp S. Murine Ex Vivo Cultured Alveolar Macrophages Provide a Novel Tool to Study Tissue-Resident Macrophage Behavior and Function. Am J Respir Cell Mol Biol 2022; 66:64-75. [PMID: 34586974 PMCID: PMC8803354 DOI: 10.1165/rcmb.2021-0190oc] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 09/28/2021] [Indexed: 11/24/2022] Open
Abstract
Tissue-resident macrophages are of vital importance as they preserve tissue homeostasis in all mammalian organs. Nevertheless, appropriate cell culture models are still limited. Here, we propose a novel culture model to study and expand murine primary alveolar macrophages (AMs), the tissue-resident macrophages of the lung, in vitro over several months. By providing a combination of granulocyte-macrophage colony-stimulating factor, TGFβ, and the PPARγ activator rosiglitazone, we maintain and expand mouse ex vivo cultured AMs (mexAMs) over several months. MexAMs maintain typical morphologic features and stably express primary AM surface markers throughout in vitro culture. They respond to microbial ligands and exhibit an AM-like transcriptional profile, including the expression of AM-specific transcription factors. Furthermore, when transferred into AM-deficient mice, mexAMs efficiently engraft in the lung and fulfill key macrophage functions, leading to a significantly reduced surfactant load in those mice. Altogether, mexAMs provide a novel, simple, and versatile tool to study AM behavior in homeostasis and disease settings.
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Affiliation(s)
- Anna-Dorothea Gorki
- Research Laboratory of Infection Biology, Department of Medicine I, and
- Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria; and
| | - Dörte Symmank
- Research Laboratory of Infection Biology, Department of Medicine I, and
- Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria; and
| | - Sophie Zahalka
- Research Laboratory of Infection Biology, Department of Medicine I, and
- Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria; and
| | - Karin Lakovits
- Research Laboratory of Infection Biology, Department of Medicine I, and
- Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria; and
| | - Anastasiya Hladik
- Research Laboratory of Infection Biology, Department of Medicine I, and
- Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria; and
| | - Brigitte Langer
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Barbara Maurer
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
| | - Veronika Sexl
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
| | - Renate Kain
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Sylvia Knapp
- Research Laboratory of Infection Biology, Department of Medicine I, and
- Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria; and
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Cao S, Schnelzer A, Hannemann N, Schett G, Soulat D, Bozec A. The Transcription Factor FRA-1/AP-1 Controls Lipocalin-2 Expression and Inflammation in Sepsis Model. Front Immunol 2021; 12:701675. [PMID: 34712224 PMCID: PMC8546226 DOI: 10.3389/fimmu.2021.701675] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 09/24/2021] [Indexed: 12/29/2022] Open
Abstract
Sepsis is a life-threatening condition characterized by excessive inflammation in its early phase. This is followed by an aberrant resolution phase associated to a prolonged period of immune suppression that can ultimately lead to multiple organ dysfunctions. This immunosuppression can be mediated by the functional reprogramming of gene transcription in monocytes/macrophages in response to prolonged lipopolysaccharide (LPS) exposure. Surprisingly, there is no report on the role of AP-1 transcription factors in this reprogramming process. Herein, we used the endotoxin tolerance model on murine bone marrow-derived macrophages in which tolerant cells stimulated twice with LPS were compared to naïve cells stimulated once. Out of all AP-1 transcription factors tested, Fosl1 gene stood out because of its unique regulation in tolerized cells. Moreover, we could correlate FRA-1 expression to the expression of an essential anti-inflammatory molecule involved in sepsis response, Lipocalin 2 aka NGAL. Identical results were obtained in human PBMC following the endotoxin tolerance model. When using FRA-1 deficient macrophages, we could confirm that FRA-1 regulates NGAL expression during the tolerant state. Interestingly, ChIP-seq and ChIP-qPCR revealed the binding of FRA-1 on Lcn2 promoter after LPS stimulation in these cells. Finally, we used an in vivo septic model of consecutive injection of LPS, in which the second stimulation is performed before the resolution of inflammation, in wild type and FRA-1 deficient mice. NGAL secretion was elevated in lung, spleen and serum of wild type tolerant mice, whereas it was significantly lower in tolerant FRA-1 deficient mice. Moreover, an increased inflammatory state likely dependent of the low level of NGAL was observed in these FRA-1 deficient mice. This was characterized by an increase of neutrophil infiltration in lung and an increase of apoptotic follicular cells in spleen. This suggests that FRA-1 expression supports resolution of inflammation in this model. Collectively, our data indicate that FRA-1 is involved in myeloid cell tolerance responses by mediating the functional reprogramming of Lcn2 transcription in response to prolonged LPS exposure. In conclusion, FRA-1 may have a protective role in the tolerance response of sepsis through the regulation of NGAL, leading to resolution of inflammation.
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Affiliation(s)
- Shan Cao
- Department of Internal Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Anne Schnelzer
- Department of Internal Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Nicole Hannemann
- Department of Internal Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.,Institute of Regenerative Medicine and Biotherapies (IRMB), University of Montpellier, INSERM U1183, Montpellier, France
| | - Georg Schett
- Department of Internal Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Didier Soulat
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Aline Bozec
- Department of Internal Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
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Guardado S, Ojeda-Juárez D, Kaul M, Nordgren TM. Comprehensive review of lipocalin 2-mediated effects in lung inflammation. Am J Physiol Lung Cell Mol Physiol 2021; 321:L726-L733. [PMID: 34468208 DOI: 10.1152/ajplung.00080.2021] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Lipocalin-2 (LCN2) is an inflammatory mediator best known for its role as an innate acute-phase protein. LCN2 mediates the innate immune response to pathogens by sequestering iron, thereby inhibiting pathogen growth. Although LCN2 and its bacteriostatic properties are well studied, other LCN2 functions in the immune response to inflammatory stimuli are less well understood, such as its role as a chemoattractant and involvement in the regulation of cell migration and apoptosis. In the lungs, most studies thus far investigating the role of LCN2 in the immune response have looked at pathogenic inflammatory stimuli. Here, we compile data that explore the role of LCN2 in the immune response to various inflammatory stimuli in an effort to differentiate between protective versus detrimental roles of LCN2.
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Affiliation(s)
- Stephanie Guardado
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, California
| | - Daniel Ojeda-Juárez
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, California
| | - Marcus Kaul
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, California
| | - Tara M Nordgren
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, California
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Du H, Liang L, Li J, Xiong Q, Yu X, Yu H. Lipocalin-2 Alleviates LPS-Induced Inflammation Through Alteration of Macrophage Properties. J Inflamm Res 2021; 14:4189-4203. [PMID: 34471375 PMCID: PMC8405166 DOI: 10.2147/jir.s328916] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 08/13/2021] [Indexed: 01/02/2023] Open
Abstract
Purpose Lipocalin-2 (Lcn2) is an acute-phase protein and elevated in several inflammatory diseases. This study aimed to determine whether Lcn2 alleviates inflammation and explore the underlying cellular mechanisms. Methods C57BL/6 Lcn2-deficient (Lcn2−/-) male mice were intraperitoneally injected with lipopolysaccharide (LPS) to build systemic inflammation model. The inflammatory processes were investigated. The morphology of villi was measured by scanning electron microscopy (SEM). The levels of inflammatory factors were detected by ELISA and qPCR analysis. The production of Lcn2 was determined with immunofluorescence staining by confocal microscope. The molecular mechanism of Lcn2 in bone marrow-derived macrophages (BMDMs) was analyzed by mass spectrometry (MS)-based quantitative proteomic analysis. Results Compared to wild-type (WT) mice injected with LPS, Lcn2−/- mice injected with LPS showed increased inflammatory damage in jejunum and ileum, and significantly elevated the levels of multiple pro-inflammatory cytokines. After determining that Lcn2 was mainly located in the cytoplasm of macrophages, we isolated BMDMs from Lcn2−/- mice to evaluate their function. During LPS challenge, transcripts of pro-inflammatory cytokines were all significantly increased in BMDMs from Lcn2−/- mice, while those of anti-inflammatory cytokines were significantly decreased when compared with the cytokines in BMDMs from WT mice. A label-free relative quantitation proteomics analysis showed that LPS-treated BMDMs from Lcn2−/- mice had elevated levels of pro-inflammatory pathways, but reduced phagocytosis and autophagy when compared with LPS-treated BMDMs from WT mice. Conclusion These findings demonstrated that Lcn2 was a potent protective factor in response to systemic inflammation and might be an indispensable factor for macrophage functions.
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Affiliation(s)
- Huahua Du
- MoE Key Laboratory of Molecular Animal Nutrition, College of Animal Science, Zhejiang University, Zhejiang, 310058, People's Republic of China
| | - Li Liang
- MoE Key Laboratory of Molecular Animal Nutrition, College of Animal Science, Zhejiang University, Zhejiang, 310058, People's Republic of China
| | - Jiahui Li
- MoE Key Laboratory of Molecular Animal Nutrition, College of Animal Science, Zhejiang University, Zhejiang, 310058, People's Republic of China
| | - Qingqing Xiong
- MoE Key Laboratory of Molecular Animal Nutrition, College of Animal Science, Zhejiang University, Zhejiang, 310058, People's Republic of China
| | - Xin Yu
- Department of Anesthesia, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Zhejiang, 310016, People's Republic of China
| | - Hong Yu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Zhejiang, 310016, People's Republic of China
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Ahn H, Lee G, Kim J, Park J, Kang SG, Yoon SI, Lee E, Lee GS. NLRP3 Triggers Attenuate Lipocalin-2 Expression Independent with Inflammasome Activation. Cells 2021; 10:cells10071660. [PMID: 34359830 PMCID: PMC8305203 DOI: 10.3390/cells10071660] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/22/2021] [Accepted: 06/29/2021] [Indexed: 11/16/2022] Open
Abstract
Lipocalin-2 (LCN2), a small secretory glycoprotein, is upregulated by toll-like receptor (TLR) signaling in various cells and tissues. LCN2 inhibits bacterial growth by iron sequestration and regulates the innate immune system. Inflammasome activates the inflammatory caspases leading to pyroptosis and cytokine maturation. This study examined the effects of inflammasome activation on LCN2 secretion in response to TLR signaling. The triggers of NLRP3 inflammasome activation attenuated LCN2 secretion while it induced interleukin-1β in mouse macrophages. In mice, NLRP3 inflammasome activation inhibited TLR-mediated LCN2 secretion. The inhibition of NLRP3 triggers on LCN2 secretion was caused by the inhibited transcription and translation of LCN2. At the same time, no changes in the other cytokines and IκBζ, a well-known transcriptional factor of Lcn2 transcription, were observed. Overall, NLRP3 triggers are a regulator of LCN2 expression suggesting a new linkage of inflammasome activation and LCN2 secretion in the innate immunity.
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Affiliation(s)
- Huijeong Ahn
- College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon, Gangwon 24341, Korea; (H.A.); (G.L.); (J.K.); (J.P.); (E.L.)
| | - Gilyoung Lee
- College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon, Gangwon 24341, Korea; (H.A.); (G.L.); (J.K.); (J.P.); (E.L.)
| | - Jeongeun Kim
- College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon, Gangwon 24341, Korea; (H.A.); (G.L.); (J.K.); (J.P.); (E.L.)
| | - Jeongho Park
- College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon, Gangwon 24341, Korea; (H.A.); (G.L.); (J.K.); (J.P.); (E.L.)
| | - Seung Goo Kang
- Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, Gangwon 24341, Korea; (S.G.K.); (S.-I.Y.)
| | - Sung-Il Yoon
- Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, Gangwon 24341, Korea; (S.G.K.); (S.-I.Y.)
| | - Eunsong Lee
- College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon, Gangwon 24341, Korea; (H.A.); (G.L.); (J.K.); (J.P.); (E.L.)
| | - Geun-Shik Lee
- College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon, Gangwon 24341, Korea; (H.A.); (G.L.); (J.K.); (J.P.); (E.L.)
- Correspondence: ; Tel.: +82-3-3250-8683; Fax: +82-3-3244-2367
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Kondreddy V, Magisetty J, Keshava S, Rao LVM, Pendurthi UR. Gab2 (Grb2-Associated Binder2) Plays a Crucial Role in Inflammatory Signaling and Endothelial Dysfunction. Arterioscler Thromb Vasc Biol 2021; 41:1987-2005. [PMID: 33827252 PMCID: PMC8147699 DOI: 10.1161/atvbaha.121.316153] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 03/19/2021] [Indexed: 01/21/2023]
Abstract
[Figure: see text].
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Affiliation(s)
- Vijay Kondreddy
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler
| | - Jhansi Magisetty
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler
| | - Shiva Keshava
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler
| | - L. Vijaya Mohan Rao
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler
| | - Usha R. Pendurthi
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler
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Ferrara F, Rial A, Suárez N, Chabalgoity JA. Polyvalent Bacterial Lysate Protects Against Pneumonia Independently of Neutrophils, IL-17A or Caspase-1 Activation. Front Immunol 2021; 12:562244. [PMID: 33981296 PMCID: PMC8108696 DOI: 10.3389/fimmu.2021.562244] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 03/18/2021] [Indexed: 11/28/2022] Open
Abstract
Polyvalent bacterial lysates have been in use for decades for prevention and treatment of respiratory infections with reported clinical benefits. However, besides claims of broad immune activation, the mode of action is still a matter of debate. The lysates, formulated with the main bacterial species involved in respiratory infections, are commonly prepared by chemical or mechanical disruption of bacterial cells, what is believed influences the biological activity of the product. Here, we prepared two polyvalent lysates with the same composition but different method of bacterial cell disruption and evaluated their biological activity in a comparative fashion. We found that both bacterial lysates induce NF-kB activation in a MyD88 dependent manner, suggesting they work as TLR agonists. Further, we found that a single intranasal dose of any of the two lysates, is sufficient to protect against pneumococcal pneumonia, suggesting that they exert similar biological activity. We have previously shown that protection against pneumococcal pneumonia can also be induced by prior S. pneumoniae sub lethal infection or therapeutic treatment with a TLR5 agonist. Protection in those cases depends on neutrophil recruitment to the lungs, and can be associated with increased local expression of IL-17A. Here, we show that bacterial lysates exert protection against pneumococcal pneumonia independently of neutrophils, IL-17A or Caspase-1/11 activation, suggesting the existence of redundant mechanisms of protection. Trypsin-treated lysates afford protection to the same extent, suggesting that just small peptides suffice to exert the protective effect or that the molecules responsible for the protective effect are not proteins. Understanding the mechanism of action of bacterial lysates and deciphering the active components shall allow redesigning them with more precisely defined formulations and expanding their range of action.
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Affiliation(s)
- Florencia Ferrara
- Laboratory for Vaccine Research, Departamento de Desarrollo Biotecnológico, Facultad de Medicina, Instituto de Higiene, Montevideo, Uruguay
| | - Analía Rial
- Laboratory for Vaccine Research, Departamento de Desarrollo Biotecnológico, Facultad de Medicina, Instituto de Higiene, Montevideo, Uruguay
| | - Norma Suárez
- Laboratory for Vaccine Research, Departamento de Desarrollo Biotecnológico, Facultad de Medicina, Instituto de Higiene, Montevideo, Uruguay
| | - José Alejandro Chabalgoity
- Laboratory for Vaccine Research, Departamento de Desarrollo Biotecnológico, Facultad de Medicina, Instituto de Higiene, Montevideo, Uruguay
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Watzenboeck ML, Drobits B, Zahalka S, Gorki AD, Farhat A, Quattrone F, Hladik A, Lakovits K, Richard GM, Lederer T, Strobl B, Versteeg GA, Boon L, Starkl P, Knapp S. Lipocalin 2 modulates dendritic cell activity and shapes immunity to influenza in a microbiome dependent manner. PLoS Pathog 2021; 17:e1009487. [PMID: 33905460 PMCID: PMC8078786 DOI: 10.1371/journal.ppat.1009487] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 03/19/2021] [Indexed: 12/27/2022] Open
Abstract
Lipocalin 2 (LCN2) is a secreted glycoprotein with roles in multiple biological processes. It contributes to host defense by interference with bacterial iron uptake and exerts immunomodulatory functions in various diseases. Here, we aimed to characterize the function of LCN2 in lung macrophages and dendritic cells (DCs) using Lcn2-/- mice. Transcriptome analysis revealed strong LCN2-related effects in CD103+ DCs during homeostasis, with differential regulation of antigen processing and presentation and antiviral immunity pathways. We next validated the relevance of LCN2 in a mouse model of influenza infection, wherein LCN2 protected from excessive weight loss and improved survival. LCN2-deficiency was associated with enlarged mediastinal lymph nodes and increased lung T cell numbers, indicating a dysregulated immune response to influenza infection. Depletion of CD8+ T cells equalized weight loss between WT and Lcn2-/- mice, proving that LCN2 protects from excessive disease morbidity by dampening CD8+ T cell responses. In vivo T cell chimerism and in vitro T cell proliferation assays indicated that improved antigen processing by CD103+ DCs, rather than T cell intrinsic effects of LCN2, contribute to the exacerbated T cell response. Considering the antibacterial potential of LCN2 and that commensal microbes can modulate antiviral immune responses, we speculated that LCN2 might cause the observed influenza phenotype via the microbiome. Comparing the lung and gut microbiome of WT and Lcn2-/- mice by 16S rRNA gene sequencing, we observed profound effects of LCN2 on gut microbial composition. Interestingly, antibiotic treatment or co-housing of WT and Lcn2-/- mice prior to influenza infection equalized lung CD8+ T cell counts, suggesting that the LCN2-related effects are mediated by the microbiome. In summary, our results highlight a novel regulatory function of LCN2 in the modulation of antiviral immunity.
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Affiliation(s)
- Martin L. Watzenboeck
- Research Laboratory of Infection Biology, Department of Medicine I, Medical University of Vienna, Austria
- CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria
| | - Barbara Drobits
- Research Laboratory of Infection Biology, Department of Medicine I, Medical University of Vienna, Austria
- CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria
| | - Sophie Zahalka
- Research Laboratory of Infection Biology, Department of Medicine I, Medical University of Vienna, Austria
- CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria
| | - Anna-Dorothea Gorki
- Research Laboratory of Infection Biology, Department of Medicine I, Medical University of Vienna, Austria
- CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria
| | - Asma Farhat
- Research Laboratory of Infection Biology, Department of Medicine I, Medical University of Vienna, Austria
- CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria
| | - Federica Quattrone
- Research Laboratory of Infection Biology, Department of Medicine I, Medical University of Vienna, Austria
- CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria
| | - Anastasiya Hladik
- Research Laboratory of Infection Biology, Department of Medicine I, Medical University of Vienna, Austria
- CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria
| | - Karin Lakovits
- Research Laboratory of Infection Biology, Department of Medicine I, Medical University of Vienna, Austria
- CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria
| | - Gabriel M. Richard
- Research Laboratory of Infection Biology, Department of Medicine I, Medical University of Vienna, Austria
- CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria
| | - Therese Lederer
- Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Birgit Strobl
- Institute of Animal Breeding and Genetics, Department of Biomedical Science, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Gijs A. Versteeg
- Department of Microbiology, Immunobiology, and Genetics, Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Vienna, Austria
| | - Louis Boon
- Polpharma Biologics, Utrecht, The Netherlands
| | - Philipp Starkl
- Research Laboratory of Infection Biology, Department of Medicine I, Medical University of Vienna, Austria
- CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria
| | - Sylvia Knapp
- Research Laboratory of Infection Biology, Department of Medicine I, Medical University of Vienna, Austria
- CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria
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Bonnard B, Martínez-Martínez E, Fernández-Celis A, Pieronne-Deperrois M, Do QT, Ramos I, Rossignol P, Zannad F, Mulder P, Ouvrard-Pascaud A, López-Andrés N, Jaisser F. Antifibrotic effect of novel neutrophil gelatinase-associated lipocalin inhibitors in cardiac and renal disease models. Sci Rep 2021; 11:2591. [PMID: 33510370 PMCID: PMC7844219 DOI: 10.1038/s41598-021-82279-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 01/19/2021] [Indexed: 11/18/2022] Open
Abstract
Neutrophil gelatinase-associated lipocalin (NGAL) is involved in cardiovascular and renal diseases. Gene inactivation of NGAL blunts the pathophysiological consequences of cardiovascular and renal damage. We aimed to design chemical NGAL inhibitors and investigate its effects in experimental models of myocardial infarction (MI) and chronic kidney disease induced by 5/6 nephrectomy (CKD) on respectively 8–12 weeks old C57Bl6/j and FVB/N male mice. Among the 32 NGAL inhibitors tested, GPZ614741 and GPZ058225 fully blocked NGAL-induced inflammatory and profibrotic markers in human cardiac fibroblasts and primary mouse kidney fibroblasts. The administration of GPZ614741 (100 mg/kg/day) for three months, was able to improve cardiac function in MI mice and reduced myocardial fibrosis and inflammation. The administration of GPZ614741 (100 mg/kg/day) for two months resulting to no renal function improvement but prevented the increase in blood pressure, renal tubulointerstitial fibrosis and profibrotic marker expression in CKD mice. In conclusion, we have identified new compounds with potent inhibitory activity on NGAL-profibrotic and pro-inflammatory effects. GPZ614741 prevented interstitial fibrosis and dysfunction associated with MI, as well as tubulointerstitial fibrosis in a CKD model. These inhibitors could be used for other diseases that involve NGAL, such as cancer or metabolic diseases, creating new therapeutic options.
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Affiliation(s)
- Benjamin Bonnard
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, 15 rue de l'Ecole de Médecine, 75006, Paris, France
| | - Ernesto Martínez-Martínez
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, 15 rue de l'Ecole de Médecine, 75006, Paris, France
| | - Amaya Fernández-Celis
- Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | | | | | - Isbaal Ramos
- Innovative Technologies in Biological Systems SL (INNOPROT), Bizkaia, Spain
| | - Patrick Rossignol
- INSERM Centre d'Investigations Cliniques-Plurithématique 1433, UMR 1116, CHRU de Nancy, French-Clinical Research Infrastructure Network (F-CRIN) INI-CRCT, Université de Lorraine, Nancy, France
| | - Faiez Zannad
- INSERM Centre d'Investigations Cliniques-Plurithématique 1433, UMR 1116, CHRU de Nancy, French-Clinical Research Infrastructure Network (F-CRIN) INI-CRCT, Université de Lorraine, Nancy, France
| | - Paul Mulder
- Inserm U1096, UFR Médecine-Pharmacie, Rouen, France
| | | | - Natalia López-Andrés
- Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.,INSERM Centre d'Investigations Cliniques-Plurithématique 1433, UMR 1116, CHRU de Nancy, French-Clinical Research Infrastructure Network (F-CRIN) INI-CRCT, Université de Lorraine, Nancy, France
| | - Frédéric Jaisser
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, 15 rue de l'Ecole de Médecine, 75006, Paris, France. .,INSERM Centre d'Investigations Cliniques-Plurithématique 1433, UMR 1116, CHRU de Nancy, French-Clinical Research Infrastructure Network (F-CRIN) INI-CRCT, Université de Lorraine, Nancy, France.
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36
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Iron in immune cell function and host defense. Semin Cell Dev Biol 2020; 115:27-36. [PMID: 33386235 DOI: 10.1016/j.semcdb.2020.12.005] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 12/17/2020] [Accepted: 12/17/2020] [Indexed: 12/13/2022]
Abstract
The control over iron availability is crucial under homeostatic conditions and even more in the case of an infection. This results from diverse properties of iron: first, iron is an important trace element for the host as well as for the pathogen for various cellular and metabolic processes, second, free iron catalyzes Fenton reaction and is therefore producing reactive oxygen species as a part of the host defense machinery, third, iron exhibits important effects on immune cell function and differentiation and fourth almost every immune activation in turn impacts on iron metabolism and spatio-temporal iron distribution. The central importance of iron in the host and microbe interplay and thus for the course of infections led to diverse strategies to restrict iron for invading pathogens. In this review, we focus on how iron restriction to the pathogen is a powerful innate immune defense mechanism of the host called "nutritional immunity". Important proteins in the iron-host-pathogen interplay will be discussed as well as the influence of iron on the efficacy of innate and adaptive immunity. Recently described processes like ferritinophagy and ferroptosis are further covered in respect to their impact on inflammation and infection control and how they impact on our understanding of the interaction of host and pathogen.
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Kangelaris KN, Clemens R, Fang X, Jauregui A, Liu T, Vessel K, Deiss T, Sinha P, Leligdowicz A, Liu KD, Zhuo H, Alder MN, Wong HR, Calfee CS, Lowell C, Matthay MA. A neutrophil subset defined by intracellular olfactomedin 4 is associated with mortality in sepsis. Am J Physiol Lung Cell Mol Physiol 2020; 320:L892-L902. [PMID: 33355521 DOI: 10.1152/ajplung.00090.2020] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Sepsis is a heterogeneous syndrome clinically and biologically, but biomarkers of distinct host response pathways for early prognostic information and testing targeted treatments are lacking. Olfactomedin 4 (OLFM4), a matrix glycoprotein of neutrophil-specific granules, defines a distinct neutrophil subset that may be an independent risk factor for poor outcomes in sepsis. We hypothesized that increased percentage of OLFM4+ neutrophils on sepsis presentation would be associated with mortality. In a single-center, prospective cohort study, we enrolled adults admitted to an academic medical center from the emergency department (ED) with suspected sepsis [identified by 2 or greater systemic inflammatory response syndrome (SIRS) criteria and antibiotic receipt] from March 2016 through December 2017, followed by sepsis adjudication according to Sepsis-3. We collected 200 µL of whole blood within 24 h of admission and stained for the neutrophil surface marker CD66b followed by intracellular staining for OLFM4 quantitated by flow cytometry. The predictors for 60-day mortality were 1) percentage of OLFM4+ neutrophils and 2) OLFM4+ neutrophils at a cut point of ≥37.6% determined by the Youden Index. Of 120 enrolled patients with suspected sepsis, 97 had sepsis and 23 had nonsepsis SIRS. The mean percentage of OLFM4+ neutrophils was significantly increased in both sepsis and nonsepsis SIRS patients who died (P ≤ 0.01). Among sepsis patients with elevated OLFM4+ (≥37.6%), 56% died, compared with 18% with OLFM4+ <37.6% (P = 0.001). The association between OLFM4+ and mortality withstood adjustment for age, sex, absolute neutrophil count, comorbidities, and standard measures of severity of illness (SOFA score, APACHE III) (P < 0.03). In summary, OLFM4+ neutrophil percentage is independently associated with 60-day mortality in sepsis and may represent a novel measure of the heterogeneity of host response to sepsis.
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Affiliation(s)
- Kirsten N Kangelaris
- Division of Hospital Medicine, Department of Medicine, University of California, San Francisco, California
| | - Regina Clemens
- Division of Hospital Medicine, Department of Medicine, University of California, San Francisco, California
| | - Xiaohui Fang
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California.,Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California
| | - Alejandra Jauregui
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California.,Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California
| | - Tom Liu
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California.,Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California
| | - Kathryn Vessel
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California.,Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California
| | - Thomas Deiss
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California.,Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California
| | - Pratik Sinha
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California.,Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California
| | - Aleksandra Leligdowicz
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California.,Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California.,Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Kathleen D Liu
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California.,Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California
| | - Hanjing Zhuo
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California.,Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California
| | - Matthew N Alder
- Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Hector R Wong
- Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Carolyn S Calfee
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California.,Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California
| | - Clifford Lowell
- Department of Laboratory Medicine, University of California, San Francisco, California
| | - Michael A Matthay
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California.,Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California
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Li G, Wang J, He X, Zhang L, Ran Q, Xiong A, Wu D, Hu L, Song Q, Zhu D. An integrative analysis identifying transcriptional features and key genes involved in COVID-19. Epigenomics 2020; 12:1969-1981. [PMID: 33242255 PMCID: PMC7714049 DOI: 10.2217/epi-2020-0168] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 09/18/2020] [Indexed: 02/03/2023] Open
Abstract
Aim: To elucidate the transcriptional characteristics of COVID-19. Materials & methods: We utilized an integrative approach to comprehensively analyze the transcriptional features of both COVID-19 patients and SARS-CoV-2 infected cells. Results: Widespread infiltration of immune cells was observed. We identified 233 genes that were codifferentially expressed in both bronchoalveolar lavage fluid and lung samples of COVID-19 patients. Functional analysis suggested upregulated genes were related to immune response such as neutrophil activation and antivirus response, while downregulated genes were associated with cell adhesion. Finally, we identified LCN2, STAT1 and UBE2L6 as core genes during SARS-CoV-2 infection. Conclusion: The identification of core genes involved in COVID-19 can provide us with more insights into the molecular features of COVID-19.
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Affiliation(s)
- Guoping Li
- Laboratory of Allergy & Inflammation, Chengdu Institute of Respiratory Health, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610031, China
- Department of Pulmonary and Critical Care Medicine, Sub-center of National Clinical Research Center for Respiratory Disease, The Third People's Hospital of Chengdu, Affiliated Hospital of Chongqing Medical University, Chengdu 610031, China
| | - Junyi Wang
- State Key Laboratory of Quality Research inChinese Medicine, Macau University of Science & Technology, Taipa, Macau(SAR), China
| | - Xiang He
- Laboratory of Allergy & Inflammation, Chengdu Institute of Respiratory Health, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610031, China
- Department of Pulmonary and Critical Care Medicine, Sub-center of National Clinical Research Center for Respiratory Disease, The Third People's Hospital of Chengdu, Affiliated Hospital of Chongqing Medical University, Chengdu 610031, China
- Department of Respiratory Disease, Sichuan Friendship Hospital, Chengdu 610000, China
| | - Lei Zhang
- Laboratory of Allergy & Inflammation, Chengdu Institute of Respiratory Health, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610031, China
- Department of Pulmonary and Critical Care Medicine, Sub-center of National Clinical Research Center for Respiratory Disease, The Third People's Hospital of Chengdu, Affiliated Hospital of Chongqing Medical University, Chengdu 610031, China
| | - Qin Ran
- Laboratory of Allergy & Inflammation, Chengdu Institute of Respiratory Health, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610031, China
- Department of Pulmonary and Critical Care Medicine, Sub-center of National Clinical Research Center for Respiratory Disease, The Third People's Hospital of Chengdu, Affiliated Hospital of Chongqing Medical University, Chengdu 610031, China
| | - Anying Xiong
- Laboratory of Allergy & Inflammation, Chengdu Institute of Respiratory Health, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610031, China
- Department of Pulmonary and Critical Care Medicine, Sub-center of National Clinical Research Center for Respiratory Disease, The Third People's Hospital of Chengdu, Affiliated Hospital of Chongqing Medical University, Chengdu 610031, China
| | - Dehong Wu
- Laboratory of Allergy & Inflammation, Chengdu Institute of Respiratory Health, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610031, China
- Department of Pulmonary and Critical Care Medicine, Sub-center of National Clinical Research Center for Respiratory Disease, The Third People's Hospital of Chengdu, Affiliated Hospital of Chongqing Medical University, Chengdu 610031, China
| | - Lingjuan Hu
- Department of RespiratoryDisease, Renshou county people's hospital, Chengdu 620550, China
| | - Qi Song
- State Key Laboratory of Quality Research inChinese Medicine, Macau University of Science & Technology, Taipa, Macau(SAR), China
| | - Dong Zhu
- State Key Laboratory of Quality Research inChinese Medicine, Macau University of Science & Technology, Taipa, Macau(SAR), China
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Gerner RR, Nuccio SP, Raffatellu M. Iron at the host-microbe interface. Mol Aspects Med 2020; 75:100895. [PMID: 32883564 PMCID: PMC7554189 DOI: 10.1016/j.mam.2020.100895] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/15/2020] [Accepted: 08/17/2020] [Indexed: 02/07/2023]
Abstract
Iron is an essential micronutrient for nearly all living organisms. In addition to facilitating redox reactions, iron is bound by metalloproteins that participate in a variety of biological processes. As the bioavailability of free iron in host environments is extremely low, iron lies at the center of a battle for nutrients between microbes and their host. Mucosal surfaces such as the respiratory and gastrointestinal tracts are constantly exposed to commensal and pathogenic microorganisms. Whereas a key strategy of mammalian antimicrobial defense is to deprive microbes of iron, pathogens and some commensals have evolved effective strategies to circumvent iron limitation. Here we provide an overview of mechanisms underpinning the tug-of-war for iron between microbes and their host, with a particular focus on mucosal surfaces.
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Affiliation(s)
- Romana R Gerner
- Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA; Division of Internal Medicine I, Department of Medicine, Innsbruck Medical University, Innsbruck, Austria
| | - Sean-Paul Nuccio
- Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
| | - Manuela Raffatellu
- Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA; Chiba University-UC San Diego Center for Mucosal Immunology, Allergy, and Vaccines (CU-UCSD CMAV), La Jolla, CA, USA.
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40
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He L, Zhang Q, Li Z, Shen L, Zhang J, Wang P, Wu S, Zhou T, Xu Q, Chen X, Fan X, Fan Y, Wang N. Incorporation of Urinary Neutrophil Gelatinase-Associated Lipocalin and Computed Tomography Quantification to Predict Acute Kidney Injury and In-Hospital Death in COVID-19 Patients. KIDNEY DISEASES 2020; 7:120-130. [PMID: 33824868 PMCID: PMC7573910 DOI: 10.1159/000511403] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 09/06/2020] [Indexed: 01/08/2023]
Abstract
Background The prevalence of acute kidney injury (AKI) in COVID-19 patients is high, with poor prognosis. Early identification of COVID-19 patients who are at risk for AKI and may develop critical illness and death is of great importance. Objective The aim of this study was to develop and validate a prognostic model of AKI and in-hospital death in patients with COVID-19, incorporating the new tubular injury biomarker urinary neutrophil gelatinase-associated lipocalin (u-NGAL) and artificial intelligence (AI)-based chest computed tomography (CT) analysis. Methods A single-center cohort of patients with COVID-19 from Wuhan Leishenshan Hospital were included in this study. Demographic characteristics, laboratory findings, and AI-assisted chest CT imaging variables identified on hospital admission were screened using least absolute shrinkage and selection operator (LASSO) and logistic regression to develop a model for predicting the AKI risk. The accuracy of the AKI prediction model was measured using the concordance index (C-index), and the internal validity of the model was assessed by bootstrap resampling. A multivariate Cox regression model and Kaplan-Meier curves were analyzed for survival analysis in COVID-19 patients. Results One hundred seventy-four patients were included. The median (±SD) age of the patients was 63.59 ± 13.79 years, and 83 (47.7%) were men.u-NGAL, serum creatinine, serum uric acid, and CT ground-glass opacity (GGO) volume were independent predictors of AKI, and all were selected in the nomogram. The prediction model was validated by internal bootstrapping resampling, showing results similar to those obtained from the original samples (i.e., 0.958; 95% CI 0.9097–0.9864). The C-index for predicting AKI was 0.955 (95% CI 0.916–0.995). Multivariate Cox proportional hazards regression confirmed that a high u-NGAL level, an increased GGO volume, and lymphopenia are strong predictors of a poor prognosis and a high risk of in-hospital death. Conclusions This model provides a useful individualized risk estimate of AKI in patients with COVID-19. Measurement of u-NGAL and AI-based chest CT quantification are worthy of application and may help clinicians to identify patients with a poor prognosis in COVID-19 at an early stage.
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Affiliation(s)
- Li He
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Qunzi Zhang
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Ze Li
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Li Shen
- Clinical Research Center, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jiayin Zhang
- Department of Radiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Peng Wang
- Department of Infection, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Shan Wu
- Department of Endoscopy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Ting Zhou
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Qiuting Xu
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xiaohua Chen
- Department of Infection, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xiaohong Fan
- Department of Pneumology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Ying Fan
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Niansong Wang
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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41
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Meyers K, López M, Ho J, Wills S, Rayalam S, Taval S. Lipocalin-2 deficiency may predispose to the progression of spontaneous age-related adiposity in mice. Sci Rep 2020; 10:14589. [PMID: 32883997 PMCID: PMC7471318 DOI: 10.1038/s41598-020-71249-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 08/13/2020] [Indexed: 01/10/2023] Open
Abstract
Lipocalin-2 (Lcn2) is an innate immune protein elevated by several orders of magnitude in various inflammatory conditions including aging and obesity. Recent studies have shown that Lcn2 is secreted by adipocytes in response to inflammation and is categorized as a new adipokine cross-linking innate immunity and metabolic disorders including obesity. However, the involvement of Lcn2 and its function during the progression of obesity is largely unknown. Recently, browning of white adipose tissue (WAT) has gained attention as a therapeutic strategy to combat obesity. Herein, we have shown that treatment of mature 3T3-L1 adipocytes with recombinant Lcn2 (rec-Lcn2) resulted in the up-regulation of thermogenic and beige/brown markers (UCP1, PRDM16, ZIC-1 and TBX1) and increased mitochondrial activity. Additionally, global Lcn2 genetic knockout (Lcn2KO) mice exhibited accelerated weight gain and visceral fat deposition with age, when compared to wild type (WT) mice. Taken together, both in vitro and in vivo studies suggest that Lcn2 is a naturally occurring adipokine, and may serve as an anti-obesity agent by upregulating the thermogenic markers resulting in the browning of WAT. Therefore, Lcn2 and its downstream signaling pathways could be a potential therapeutic target for obesity.
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Affiliation(s)
- Keya Meyers
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine - Georgia Campus, 625 Old Peachtree Road, Suwanee, GA, 30024, USA
| | - María López
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine - Georgia Campus, 625 Old Peachtree Road, Suwanee, GA, 30024, USA
| | - Joanna Ho
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine - Georgia Campus, 625 Old Peachtree Road, Suwanee, GA, 30024, USA
| | - Savannah Wills
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine - Georgia Campus, 625 Old Peachtree Road, Suwanee, GA, 30024, USA
| | - Srujana Rayalam
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine - Georgia Campus, 625 Old Peachtree Road, Suwanee, GA, 30024, USA. .,Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine, Room 3040, 625 Old Peachtree Road, Suwanee, GA, 30024, USA.
| | - Shashidharamurthy Taval
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine - Georgia Campus, 625 Old Peachtree Road, Suwanee, GA, 30024, USA. .,Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine, Room 3031, 625 Old Peachtree Road, Suwanee, GA, 30024, USA.
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42
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Ramezani Kapourchali F, Glueck B, Han Y, Shapiro D, Fulmer CG, Cresci GAM. A Spore-Forming Probiotic Supplement Improves the Intestinal Immune Response and Protects the Intestinal Health During Recurrent Clostridioides difficile Colonization in Mice. JPEN J Parenter Enteral Nutr 2020; 44:1428-1438. [PMID: 32495964 DOI: 10.1002/jpen.1851] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 04/14/2020] [Indexed: 11/11/2022]
Abstract
BACKGROUND Around 15%-30% of patients develop recurrent Clostridioides difficile infection (CDI) as conventional therapies disrupt protective gut microbiota. We tested if supplementation with a spore-forming probiotic would protect intestinal health in a mouse model of recurrent CD colonization. METHODS Methods: Female CF-1 mice were exposed to CD spores (4-log10 colony-forming units/10 μL) and then randomly assigned to receive either saline (CD-S) or probiotic (CD-PRO). Control mice received only saline (control). Following confirmation of initial CD colonization, mice were treated with vancomycin (10 days). After 5 days, mice recolonized with CD were treated again with vancomycin (10 days) and euthanized 5 days later. Fecal samples were collected at select time points for bacterial analysis. Following euthanasia, blood samples, cecum contents, and the intestine were collected for analysis. RESULTS Probiotic supplementation mitigated the antibiotic-induced changes in cecum weight (P < .001). Probiotic-supplemented mice had increased messenger RNA expression of several immune parameters, accompanied by lower serum iron levels compared with CD-S mice (P < .05). Lower expressions of TNF α and calprotectin (P ≤ .05) were observed in CD-PRO mice compared with CD-S. The probiotics also supported the expression of intestinal tight junction proteins, which were diminished in the proximal colon of CD-S mice (P < .05). CONCLUSION Mice supplemented with targeted spore-forming probiotics exhibited improved immune responses and nutrition immunity properties, which were linked with less inflammation and enhanced intestinal barrier proteins during recurrent CD colonization.
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Affiliation(s)
| | - Bryan Glueck
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
| | - Yingchun Han
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
| | - David Shapiro
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
| | - Clifton G Fulmer
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Gail A M Cresci
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Pediatric Gastroenterology, Cleveland Clinic, Cleveland, Ohio, USA.,Center for Human Nutrition, Cleveland Clinic, Cleveland, Ohio, USA
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Abstract
Metabolism is one of the strongest drivers of interkingdom interactions-including those between microorganisms and their multicellular hosts. Traditionally thought to fuel energy requirements and provide building blocks for biosynthetic pathways, metabolism is now appreciated for its role in providing metabolites, small-molecule intermediates generated from metabolic processes, to perform various regulatory functions to mediate symbiotic relationships between microbes and their hosts. Here, we review recent advances in our mechanistic understanding of how microbiota-derived metabolites orchestrate and support physiological responses in the host, including immunity, inflammation, defense against infections, and metabolism. Understanding how microbes metabolically communicate with their hosts will provide us an opportunity to better describe how a host interacts with all microbes-beneficial, pathogenic, and commensal-and an opportunity to discover new ways to treat microbial-driven diseases.
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Affiliation(s)
- Justin L McCarville
- Molecular and Systems Physiology Laboratory, Gene Expression Laboratory, NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, California 92037, USA;
| | - Grischa Y Chen
- Molecular and Systems Physiology Laboratory, Gene Expression Laboratory, NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, California 92037, USA;
| | - Víctor D Cuevas
- Molecular and Systems Physiology Laboratory, Gene Expression Laboratory, NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, California 92037, USA;
| | - Katia Troha
- Molecular and Systems Physiology Laboratory, Gene Expression Laboratory, NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, California 92037, USA;
| | - Janelle S Ayres
- Molecular and Systems Physiology Laboratory, Gene Expression Laboratory, NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, California 92037, USA;
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44
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Lei W, Zeng H, Feng H, Ru X, Li Q, Xiao M, Zheng H, Chen Y, Zhang L. Development of an Early Prediction Model for Subarachnoid Hemorrhage With Genetic and Signaling Pathway Analysis. Front Genet 2020; 11:391. [PMID: 32373167 PMCID: PMC7186496 DOI: 10.3389/fgene.2020.00391] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Accepted: 03/30/2020] [Indexed: 01/15/2023] Open
Abstract
Subarachnoid hemorrhage (SAH) is devastating disease with high mortality, high disability rate, and poor clinical prognosis. It has drawn great attentions in both basic and clinical medicine. Therefore, it is necessary to explore the therapeutic drugs and effective targets for early prediction of SAH. Firstly, we demonstrate that LCN2 can effectively intervene or treat SAH from the perspective of cell signaling pathway. Next, three potential genes that we explored have been validated by manually reviewed experimental evidences. Finally, we turn out that the SAH early ensemble learning predictive model performs better than the classical LR, SVM, and Naïve-Bayes models.
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Affiliation(s)
- Wanjing Lei
- College of Computer Science, Sichuan University, Chengdu, China
| | - Han Zeng
- College of Computer and Information Science, Southwest University, Chongqing, China
| | - Hua Feng
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University, Chongqing, China
| | - Xufang Ru
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University, Chongqing, China
| | - Qiang Li
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University, Chongqing, China
| | - Ming Xiao
- College of Computer Science, Sichuan University, Chengdu, China
| | - Huiru Zheng
- School of Computing, Ulster University, Coleraine, United Kingdom
| | - Yujie Chen
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University, Chongqing, China
| | - Le Zhang
- College of Computer Science, Sichuan University, Chengdu, China
- College of Computer and Information Science, Southwest University, Chongqing, China
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Ghosh S, Stepicheva N, Yazdankhah M, Shang P, Watson AM, Hose S, Liu H, Weiss J, Zigler JS, Valapala M, Watkins SC, Sinha D. The role of lipocalin-2 in age-related macular degeneration (AMD). Cell Mol Life Sci 2020; 77:835-851. [PMID: 31901947 PMCID: PMC7079812 DOI: 10.1007/s00018-019-03423-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 12/04/2019] [Accepted: 12/10/2019] [Indexed: 12/21/2022]
Abstract
Lipocalins are a family of secreted adipokines which play important roles in various biological processes. Lipocalin-2 (LCN-2) has been shown to be involved in acute and chronic inflammation. This particular protein is critical in the pathogenesis of several diseases including cancer, diabetes, obesity, and multiple sclerosis. Herein, we discuss the general molecular basis for the involvement of LCN-2 in acute infections and chronic disease progression and also ascertain the probable role of LCN-2 in ocular diseases, particularly in age-related macular degeneration (AMD). We elaborate on the signaling cascades which trigger LCN-2 upregulation in AMD and suggest therapeutic strategies for targeting such pathways.
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Affiliation(s)
- Sayan Ghosh
- Department of Ophthalmology, Children's Hospital of University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
| | - Nadezda Stepicheva
- Department of Ophthalmology, Children's Hospital of University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA
| | - Meysam Yazdankhah
- Department of Ophthalmology, Children's Hospital of University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA
| | - Peng Shang
- Department of Ophthalmology, Children's Hospital of University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA
| | - Alan M Watson
- Center for Biologic Imaging and Department of Cellular Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Stacey Hose
- Department of Ophthalmology, Children's Hospital of University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA
| | - Haitao Liu
- Department of Ophthalmology, Children's Hospital of University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA
| | - Joseph Weiss
- Department of Ophthalmology, Children's Hospital of University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA
| | - J Samuel Zigler
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Simon C Watkins
- Center for Biologic Imaging and Department of Cellular Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Debasish Sinha
- Department of Ophthalmology, Children's Hospital of University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Ophthalmology, Cell Biology and Developmental Biology, Children's Hospital of University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
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Yin C, Jia X, Zhao Q, Zhao Z, Wang J, Zhang Y, Li Z, Sun H, Li Z. Transcription factor 7-like 2 promotes osteogenic differentiation and boron-induced bone repair via lipocalin 2. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 110:110671. [PMID: 32204099 DOI: 10.1016/j.msec.2020.110671] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 01/12/2020] [Accepted: 01/14/2020] [Indexed: 01/07/2023]
Abstract
Boron-containing mesoporous bioactive glass (B-MBG) scaffolds could be capable of promoting osteogenesis by activating Wnt/β-catenin signaling pathway during the process of bone defect repair. Despite this, more involving molecular controls are still largely unclear. In the present study, we identified that the downstream of Wnt/β-catenin signaling pathway named transcription factor 7-like 2 (TCF7L2) served as a key effector to promote boron-induced bone regeneration and osteogenesis through lipocalin 2 (LCN2). TCF7L2 was highly expressed in osteoblasts when treated with B-MBG scaffold extraction than MBG. LCN2, as a secreted bone factor, positively affected osteogenic differentiation of MC3T3-E1 and osteogenesis in vivo, which could be induced by TCF7L2. In addition, interference of TCF7L2 decreased the osteogenic differentiation of osteoblasts. Finally, we identified that rLCN2 could rescue the poor ability of osteogenic differentiation of MC3T3-E1 whose Tcf7l2 gene was knocked down by lentiviral transfection of shRNA. Our findings provide some new insights into the molecular controls of boron-associated bone regeneration and potential therapeutic targets for the treatment of bone defects.
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Affiliation(s)
- Chengcheng Yin
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang 110002, China
| | - Xiaoshi Jia
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Qin Zhao
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Zifan Zhao
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Jinyang Wang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Yufeng Zhang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Zhi Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
| | - Hongchen Sun
- School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang 110002, China.
| | - Zubing Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
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Galeas-Pena M, McLaughlin N, Pociask D. The role of the innate immune system on pulmonary infections. Biol Chem 2019; 400:443-456. [PMID: 29604208 DOI: 10.1515/hsz-2018-0304] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 09/19/2018] [Indexed: 12/15/2022]
Abstract
Inhalation is required for respiration and life in all vertebrates. This process is not without risk, as it potentially exposes the host to environmental pathogens with every breath. This makes the upper respiratory tract one of the most common routes of infection and one of the leading causes of morbidity and mortality in the world. To combat this, the lung relies on the innate immune defenses. In contrast to the adaptive immune system, the innate immune system does not require sensitization, previous exposure or priming to attack foreign particles. In the lung, the innate immune response starts with the epithelial barrier and mucus production and is reinforced by phagocytic cells and T cells. These cells are vital for the production of cytokines, chemokines and anti-microbial peptides that are critical for clearance of infectious agents. In this review, we discuss all aspects of the innate immune response, with a special emphasis on ways to target aspects of the immune response to combat antibiotic resistant bacteria.
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Affiliation(s)
- Michelle Galeas-Pena
- Department of Pulmonary Critical Care and Environmental Medicine, Tulane University School of Medicine, 333 S. Liberty St., New Orleans, LA 70112, USA
| | - Nathaniel McLaughlin
- Department of Pulmonary Critical Care and Environmental Medicine, Tulane University School of Medicine, 333 S. Liberty St., New Orleans, LA 70112, USA
| | - Derek Pociask
- Department of Pulmonary Critical Care and Environmental Medicine, Tulane University School of Medicine, 333 S. Liberty St., New Orleans, LA 70112, USA
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Wang Q, Li S, Tang X, Liang L, Wang F, Du H. Lipocalin 2 Protects Against Escherichia coli Infection by Modulating Neutrophil and Macrophage Function. Front Immunol 2019; 10:2594. [PMID: 31781104 PMCID: PMC6857527 DOI: 10.3389/fimmu.2019.02594] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 10/21/2019] [Indexed: 12/22/2022] Open
Abstract
Lipocalin 2 (Lcn2) is an essential component of the antimicrobial innate immune system. It attenuates bacterial growth by binding and sequestering the iron-scavenging siderophores to prevent bacterial iron acquisition. Whereas, the ability of Lcn2 to sequester iron is well-described, the role of Lcn2 in regulating immune cells during bacterial infection remains unclear. In this study, we showed that upon infection with Escherichia coli (O157:H7), Lcn2-deficient (Lcn2 -/-) mice carried more bacteria in blood and liver, and the acute-phase sera lost their antibacterial activity in vitro. Neutrophils from Lcn2 -/- mice were defective in homeostasis and morphological development. E. coli O157:H7 infection of Lcn2 -/- mice resulted in a reduced neutrophil migration capacity, with 30% reduction of extravasated neutrophils, and impaired chemotaxis, as shown by a reduction in the secretion of chemoattractants, such as tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-2, which are instrumental in eliciting a neutrophil response. We also found that some secreted cytokines [interleukin (IL)-6, IL-1β, and TNF-α] were decreased. Transcripts of inflammatory cytokines (IL-6, IL-1β, TNF-α, and IL-10), chemokines (MIP-2 and MCP-1), and iNOS production were all strongly repressed in Lcn2 -/- macrophages. Furthermore, Lcn2 could induce the production of chemokines and promote the migration and phagocytosis of macrophages. Thus, Lcn2 deficiency could impair the migration and chemotaxis ability of neutrophils and disturb the normal secretion of inflammatory cytokines of macrophages. Therefore, the heightened sensitivity of Lcn2 -/- mice to E. coli O157:H7 is not only due to the antibacterial function of Lcn2 but also a consequence of impaired functions of immune cells, including neutrophils and macrophages.
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Affiliation(s)
- Qianqian Wang
- MoE Key Laboratory of Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Shuhui Li
- MoE Key Laboratory of Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Xueyou Tang
- MoE Key Laboratory of Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Li Liang
- MoE Key Laboratory of Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Fengqin Wang
- MoE Key Laboratory of Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Huahua Du
- MoE Key Laboratory of Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, China
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Li D, Yan Sun W, Fu B, Xu A, Wang Y. Lipocalin-2-The myth of its expression and function. Basic Clin Pharmacol Toxicol 2019; 127:142-151. [PMID: 31597008 DOI: 10.1111/bcpt.13332] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 09/19/2019] [Indexed: 01/01/2023]
Abstract
Lipocalin-2 is a functional biomarker for acute and chronic kidney diseases, heart failure and obesity-related medical complications. It is rapidly induced in epithelial cells under stress conditions, but constitutively produced from pre-adipocytes and mature adipocytes. Measuring the lipocalin-2 levels represents an effective approach for risk prediction, patient stratification and disease management. Nevertheless, due to ligand-binding, post-translational modification and protein-protein interaction, lipocalin-2 exists as multiple variants that elicit different pathophysiological functions. To characterize the specific structure-functional relationships of lipocalin-2 variants is critical for the development of biomarker assays with sufficient precision and reliability. Moreover, identifying the pathological forms of lipocalin-2 will provide new therapeutic targets and treatment approaches for obesity-related complications.
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Affiliation(s)
- Dahui Li
- The State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China
| | - Wai Yan Sun
- The State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China
| | - Bowen Fu
- The State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China
| | - Aimin Xu
- The State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China
| | - Yu Wang
- The State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China
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Paukszto L, Mikolajczyk A, Szeszko K, Smolinska N, Jastrzebski JP, Kaminski T. Transcription analysis of the response of the porcine adrenal cortex to a single subclinical dose of lipopolysaccharide from Salmonella Enteritidis. Int J Biol Macromol 2019; 141:1228-1245. [PMID: 31520703 DOI: 10.1016/j.ijbiomac.2019.09.067] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/03/2019] [Accepted: 09/09/2019] [Indexed: 12/20/2022]
Abstract
Lipopolysaccharide (LPS) is a bacterial endotoxin which can participate in the induction of inflammatory responses. LPS may also play a significant role in some neurodegenerative, oncological and metabolic disorders. The aim of the current study was to determine the effect of a subclinical low single dose of LPS from Salmonella Enteritidis administrated in vivo on the transcriptome of porcine adrenal cortex cells, especially gene expression levels, long non-coding RNA (lncRNA) profiles, alternative splicing events and RNA editing sites using RNA-seq technology. The subclinical dose of LPS changed the expression of 354 genes, 27 lncRNA loci and other unclassified RNAs. An analysis of alternative splicing events revealed 104 genes with differentially expressed splice junction sites, and the single nucleotide variant calling approach supported the identification of 376 canonical RNA editing candidates and 7249 allele-specific expression variants. The obtained results suggest that the RIG-I-like receptor signaling pathway, may play a more important role than the Toll-like signaling pathway after the administration of a subclinical dose of LPS. Single subclinical dose of LPS can affect the expression profiles of genes coding peptide hormones, steroidogenic enzymes and transcriptional factors, and modulate the endocrine functions of the gland.
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Affiliation(s)
- Lukasz Paukszto
- Department of Plant Physiology, Genetics and Biotechnology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland.
| | - Anita Mikolajczyk
- Department of Public Health, Faculty of Health Sciences, Collegium Medicum, University of Warmia and Mazury in Olsztyn, Warszawska 30, 10-082 Olsztyn, Poland.
| | - Karol Szeszko
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland
| | - Nina Smolinska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland.
| | - Jan P Jastrzebski
- Department of Plant Physiology, Genetics and Biotechnology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland
| | - Tadeusz Kaminski
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland.
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